Timing and Intertemporal Choice Behavior in the Valproic Acid Rat Model of Autism Spectrum Disorder
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| Title: | Timing and Intertemporal Choice Behavior in the Valproic Acid Rat Model of Autism Spectrum Disorder |
|---|---|
| Language: | English |
| Authors: | DeCoteau, William E., Fox, Adam E. (ORCID |
| Source: | Journal of Autism and Developmental Disorders. Jun 2022 52(6):2414-2429. |
| Availability: | Springer. Available from: Springer Nature. One New York Plaza, Suite 4600, New York, NY 10004. Tel: 800-777-4643; Tel: 212-460-1500; Fax: 212-460-1700; e-mail: customerservice@springernature.com; Web site: https://link.springer.com/ |
| Peer Reviewed: | Y |
| Page Count: | 16 |
| Publication Date: | 2022 |
| Document Type: | Journal Articles Reports - Research |
| Descriptors: | Autism, Pervasive Developmental Disorders, Time Perspective, Animals, Motor Reactions, Intervals, Animal Behavior, Anxiety, Memory, Persistence |
| DOI: | 10.1007/s10803-021-05129-y |
| ISSN: | 0162-3257 |
| Abstract: | Recently it has been proposed that impairments related to autism spectrum disorder (ASD) may reflect a more fundamental disruption in time perception. Here, we examined whether in utero exposure to valproic acid (VPA) can generate specific behavioral deficits related to ASD and time perception. Pups from control and VPA groups were tested using fixed-interval (FI) temporal bisection, peak interval, and intertemporal choice tasks. In addition, the rats were assessed on motor function, perseverative and exploratory behavior, anxiety, and memory. The VPA group displayed a leftward shift in timing functions. VPA rats displayed no deficits on the motor and memory tasks, but were significantly different from controls on measures of perseveration and anxiety. |
| Abstractor: | As Provided |
| Entry Date: | 2022 |
| Accession Number: | EJ1335893 |
| Database: | ERIC |
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| FullText | Links: – Type: pdflink Url: https://content.ebscohost.com/cds/retrieve?content=AQICAHj0k_4E0hTGH8RJwT4gCJyBsGNe_WN95AvKlDbXJGqwxwFIFaAa0fzn18KxfWUaJ8m-AAAA4zCB4AYJKoZIhvcNAQcGoIHSMIHPAgEAMIHJBgkqhkiG9w0BBwEwHgYJYIZIAWUDBAEuMBEEDLAVMxoIrYu0JFYBzwIBEICBmziBZNCuWvk00ZCmExckk5_gJcsWHPJ6PhstPwbnBqeBUUXvWrXJPaWxC9DLmI3yh79NU8fo9ynKeG-1FPj-xEci_T8mh5Gfi0k-CeVr9So3NrRWarwY6QfRxtpcJ9nQhr0EJLXL1f14gPzbAsWqMwBERM1VYu4wmr11bo3a21sB3w-90W8MZuV6zjPKOJXlSRy-kaI8btRbFCzz Text: Availability: 1 Value: <anid>AN0156930240;aut01jun.22;2022May20.06:32;v2.2.500</anid> <title id="AN0156930240-1">Timing and Intertemporal Choice Behavior in the Valproic Acid Rat Model of Autism Spectrum Disorder </title> <p>Recently it has been proposed that impairments related to autism spectrum disorder (ASD) may reflect a more fundamental disruption in time perception. Here, we examined whether in utero exposure to valproic acid (VPA) can generate specific behavioral deficits related to ASD and time perception. Pups from control and VPA groups were tested using fixed-interval (FI) temporal bisection, peak interval, and intertemporal choice tasks. In addition, the rats were assessed on motor function, perseverative and exploratory behavior, anxiety, and memory. The VPA group displayed a leftward shift in timing functions. VPA rats displayed no deficits on the motor and memory tasks, but were significantly different from controls on measures of perseveration and anxiety.</p> <p>Keywords: Autism spectrum disorder (ASD); Delay discounting; Timing; Time perception; Rats; Valproic Acid</p> <hd id="AN0156930240-2">Introduction</hd> <p>Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with an estimated prevalence of ~ 1.7% in developed countries (Christensen et al., [<reflink idref="bib25" id="ref1">25</reflink>]; Knopf, [<reflink idref="bib68" id="ref2">68</reflink>]), and estimated annual societal cost of approximately $268 billion (Leigh &amp; Du, [<reflink idref="bib74" id="ref3">74</reflink>]; see also Rogge &amp; Janssen, [<reflink idref="bib97" id="ref4">97</reflink>]). It has no known single etiology. Identified risk factors include inherited and spontaneous genetic mutations as well as a host of environmental influences ranging from prenatal and perinatal factors to maternal dietary and lifestyle factors (e.g., Hertz‐Picciotto et al., [<reflink idref="bib58" id="ref5">58</reflink>]; Wiśniowiecka-Kowalnik &amp; Nowakowska, [<reflink idref="bib114" id="ref6">114</reflink>]). Symptoms of the disorder across individuals can vary in terms of their characteristics, onset, and the degree to which they impair daily functioning. Despite this phenotypic heterogeneity, two sets of core diagnostic features of ASD have been identified (American Psychiatric Association, [<reflink idref="bib9" id="ref7">9</reflink>]). The first core criteria is persistent social communication and social interaction deficits that can include a lack of social-emotional reciprocity, poor verbal and non-verbal communication, and the inability to establish and maintain relationships with others. The second core criteria is the presence of repetitive and restricted patterns of behavior such as stereotyped movement and speech, rigid thinking and behavior that is intolerant to change, abnormally fixed attention on specific stimuli, and impaired processing of sensory inputs. In addition to these core symptoms, a wide range of secondary social, cognitive, emotional, and motor impairments may also be present. For example, neuropsychological assessments of those diagnosed with ASD have revealed speech and language delays (e.g., Delehanty et al., [<reflink idref="bib30" id="ref8">30</reflink>]), working memory and planning deficits (e.g., Habib et al., [<reflink idref="bib54" id="ref9">54</reflink>]), impaired facial recognition (e.g., Lewis et al., [<reflink idref="bib75" id="ref10">75</reflink>]), and motor skill abnormalities (e.g., MacDonald et al., [<reflink idref="bib77" id="ref11">77</reflink>]). ASD is also often comorbid with several other psychiatric diagnoses, with anxiety being the most common (Simonoff et al., [<reflink idref="bib104" id="ref12">104</reflink>]; Underwood et al., [<reflink idref="bib108" id="ref13">108</reflink>]).</p> <p>Delineating principal phenomena responsible for a wide variety of symptoms of ASD has been understandably difficult. One approach to understanding the complex profile of ASD is to pinpoint a fundamental neurocognitive disruption that may, on its own, contribute to an array of symptoms. For example, the "theory of mind" model suggests that the diminished ability to speculate on the content of others' "minds" impairs social interactions in multiple ways and leads to social isolation (Baron-Cohen et al., [<reflink idref="bib16" id="ref14">16</reflink>]; Warrier &amp; Baron-Cohen, [<reflink idref="bib111" id="ref15">111</reflink>]). Similarly, a wide array of ASD symptoms may be accounted for by underlying executive dysfunction (Demetriou et al., [<reflink idref="bib31" id="ref16">31</reflink>]) or motor dyspraxia (e.g., Cassidy et al., [<reflink idref="bib21" id="ref17">21</reflink>]; Dziuk et al., [<reflink idref="bib33" id="ref18">33</reflink>]). Of particular interest to the present paper, is the mounting evidence that multiple ASD symptoms may reflect a basic disruption in time perception (Allman, [<reflink idref="bib2" id="ref19">2</reflink>]; Allman &amp; Mareschal, [<reflink idref="bib4" id="ref20">4</reflink>]; Falter et al., [<reflink idref="bib38" id="ref21">38</reflink>]; Isaksson et al., [<reflink idref="bib59" id="ref22">59</reflink>]; Lambrechts et al., [<reflink idref="bib70" id="ref23">70</reflink>]; Martin et al., [<reflink idref="bib83" id="ref24">83</reflink>]; Vogel et al., [<reflink idref="bib109" id="ref25">109</reflink>]). Recently, Isaksson et al. ([<reflink idref="bib59" id="ref26">59</reflink>]) assessed a sample of ASD participants on a battery of tasks that assessed motor timing, perceptual timing, and temporal perspective on a variety of time scales. Their participants displayed impairments across a wide array of timing tasks, providing perhaps the strongest evidence to date of a generalized temporal processing abnormality in ASD. Others have also suggested that disruptions in interval timing (timing durations in the seconds to hours range) accuracy and precision represent an underlying core clinical symptom of ASD (Allman, [<reflink idref="bib2" id="ref27">2</reflink>]; Allman &amp; Falter, [<reflink idref="bib3" id="ref28">3</reflink>]; Allman &amp; Meck, [<reflink idref="bib5" id="ref29">5</reflink>]; Allman et al., [<reflink idref="bib6" id="ref30">6</reflink>]) that is responsible for a wide array of behavioral and cognitive deficits.</p> <p>Despite the compelling evidence for a general timing impairment in ASD, the neurophysiological process underlying this disruption is largely unknown. Animal models are a valuable tool for elucidating behavioral and neurobiological mechanisms of human mental disorders—because the etiology of ASD involves both genetic and environmental factors, animal models have generally involved either generating rodents with targeted genetic mutations or deletions connected to ASD or exposing rodents pre- or post-natally to toxins linked to ASD (see for review Ergaz et al., [<reflink idref="bib37" id="ref31">37</reflink>]). Of the environmental agents associated with ASD, valproic acid (VPA) has been studied most extensively. VPA is an anticonvulsant and mood-stabilizing drug, primarily used for the treatment of epilepsy. The offspring of women taking VPA during early pregnancy have an increased risk of being diagnosed with ASD (Clayton-Smith &amp; Donnai, [<reflink idref="bib27" id="ref32">27</reflink>]; Moore et al., [<reflink idref="bib86" id="ref33">86</reflink>]; Williams et al., [<reflink idref="bib112" id="ref34">112</reflink>]). Rats prenatally exposed to VPA exhibit analogous anatomical malformations and developmental deficits to those observed in children with ASD, including decreased social interaction and increased repetitive/stereotypic behavior, which are the main diagnostic criteria for the disorder, and increased anxiety-like behavior, which is a common comorbidity in humans (Bambini-Junior et al., [<reflink idref="bib13" id="ref35">13</reflink>]; Banji et al., [<reflink idref="bib14" id="ref36">14</reflink>]; Chomiak et al., [<reflink idref="bib23" id="ref37">23</reflink>], [<reflink idref="bib24" id="ref38">24</reflink>]; Favre et al., [<reflink idref="bib40" id="ref39">40</reflink>]; Fontes-Dutra et al., [<reflink idref="bib41" id="ref40">41</reflink>]; Kerr et al., [<reflink idref="bib63" id="ref41">63</reflink>]; Kim et al., [<reflink idref="bib67" id="ref42">67</reflink>]; Mabunga et al., [<reflink idref="bib76" id="ref43">76</reflink>]; Markram et al., [<reflink idref="bib82" id="ref44">82</reflink>]; Mychasiuk et al., [<reflink idref="bib89" id="ref45">89</reflink>]; Reynard, [<reflink idref="bib96" id="ref46">96</reflink>]; Schneider &amp; Przewlocki, [<reflink idref="bib100" id="ref47">100</reflink>]; Schneider et al., [<reflink idref="bib102" id="ref48">102</reflink>]).</p> <p>Owing to this high construct and face validity, the VPA model is a well-established rodent analogue to ASD. However, despite its wide use, the temporal processing dynamics of the VPA model have not been investigated much. This is surprising, given that brain regions, dopaminergic systems in particular, associated with timing and ASD may also be affected by prenatal VPA exposure (Allman &amp; Meck, [<reflink idref="bib5" id="ref49">5</reflink>]; Allman et al., [<reflink idref="bib7" id="ref50">7</reflink>], [<reflink idref="bib8" id="ref51">8</reflink>]; Coull et al., [<reflink idref="bib28" id="ref52">28</reflink>]). One recent paper reported deficits in timing accuracy and precision in mice prenatally exposed to VPA (Acosta et al., [<reflink idref="bib1" id="ref53">1</reflink>]); however, those animals were not tested on tasks designed to measure ASD-like behavior as well (e.g., social interaction, stereotypy, anxiety, etc.), so the link between ASD, VPA, and timing remains uncertain in the model. Operant tasks are particularly well suited for testing time perception in rodent models, because they allow for extended testing across a wide range of parameters and comparisons can be made both during acquisition and at steady state (e.g., Fox et al., [<reflink idref="bib46" id="ref54">46</reflink>], [<reflink idref="bib47" id="ref55">47</reflink>]; Kaiser, [<reflink idref="bib61" id="ref56">61</reflink>]; Macdonald et al., [<reflink idref="bib78" id="ref57">78</reflink>]). Performance on these tasks is well established, making interpretation and comparison of normal and abnormal behavior more straightforward (Allman et al., [<reflink idref="bib6" id="ref58">6</reflink>]; Allman &amp; Meck, [<reflink idref="bib5" id="ref59">5</reflink>]; Balci et al., [<reflink idref="bib12" id="ref60">12</reflink>]; Fox &amp; Kyonka, [<reflink idref="bib43" id="ref61">43</reflink>]; Fox et al., [<reflink idref="bib45" id="ref62">45</reflink>]). The aim of the present study was to utilize timing and intertemporal choice tasks to characterize timing behavior in the VPA model. We also sought to validate the model with respect to diagnostic criteria in humans, so rats were also assessed on a series of tasks that assess motor, emotional, and executive function.</p> <hd id="AN0156930240-3">Methods</hd> <p></p> <hd id="AN0156930240-4">Animals and Experimental Timeline</hd> <p>Twelve pregnant female Wistar rats were obtain from Charles River Laboratories five days into gestation. On gestation day 12.5, pregnant rats were injected with either vehicle (n = 2) or VPA (n = 10; 500 mg/kg, i.p.) dissolved in normal saline. More VPA dams were included because past research in our lab and others (e.g., Favre et al., [<reflink idref="bib40" id="ref63">40</reflink>]) suggested a high reabsorption rate (i.e. miscarriage) in dams injected with VPA. Testing was conducted on male pups (n = 10 vehicle; 22 VPA). Litters were not culled. At approximately 21 days old, pups were weaned and pair housed with pups of the same sex from the same in utero exposure group. Only results from male offspring are presented due to unequal distribution of sexes.</p> <p>Home cages were 46 (long) × 25 (wide) × 21 (tall) cm and made of translucent polypropylene and bedded with beta chips. Enrichment was provided in the form of plastic chew toys, cardboard tubes, and paper towel. There was a 12/12 h light/dark cycle with lights on at 8 a.m. Testing was conducted during the light phase. All rats had free access to water in the home cage for the duration of the experiment. During operant testing (see below) rats were food restricted to approximately 85% of their free-feeding weight as determined by their weight pre-food restriction and growth curves provided by Charles River. All experimental procedures were approved by the Institutional Animal Care and Use Committee at St. Lawrence University. A timeline of the experiment is shown in Fig. 1. Testing began at approximately postnatal day (PND) 25.</p> <p>Graph: Fig. 1 Experimental timeline</p> <hd id="AN0156930240-5">Procedure and Apparatuses</hd> <p></p> <hd id="AN0156930240-6">Rotarod (PND 25–30)</hd> <p>The rotarod treadmill (MED Associates) consisted of a computer-controlled motor-driven drum that accelerated from 4 to 40 rpm over 5 min. All rats were tested once a day for three consecutive days. The apparatus was cleaned with an animal care disinfectant between trials. The median latency to fall across the 3 trials was used as the dependent measure for each rat. Each trial had a maximum duration of 10 min in order to test both motor coordination and endurance.</p> <hd id="AN0156930240-7">Y-Maze (PND 31–33)</hd> <p>The Y-maze apparatus was constructed of grey PVC plastic and consisted of three arms (measuring 50 cm long × 16 cm wide × 32 cm tall) radiating from each other at 120 degree angles. The entryway to each arm could be closed by inserting a grey PVC sliding door. Prominent visual cues were placed on the walls surrounding the maze and an opaque curtain separated the apparatus from the data collection computer. A ceiling mounted camera enabled trials to be observed, recorded, and analyzed using Anymaze software. All rats were given two trials. In the first trial, one arm was designated as the start arm. Rats were placed in the maze at the end of the start arm facing the end wall. One of the other two arms of the maze was randomly blocked off. Rats were then allowed to explore freely this reduced, two-arm, maze for 3 min, after which time they were returned to their home cage. Sixty minutes later, all three arms were opened, the rat was placed in the original start arm and allowed to re-explore the maze for 3 min. The apparatus was cleaned with an animal care disinfectant between all trials. Distance traveled in the maze on both the first and second trials as well as number and duration of entries into the newly opened arm on the second trial were used as the dependent measures.</p> <hd id="AN0156930240-8">Activity Task (PND 34–38)</hd> <p>This task used an activity box made of gray PVC plastic (60 × 60 cm floor and 40 cm high walls). A ceiling mounted camera enabled trials to be observed, recorded, and analyzed using Anymaze software. Testing involved a 5 min activity trial. During a trial, animals were placed individually in the center of the test box. Anymaze tracking software was used to virtually divide the field into nine equal-sized square zones including one central and eight peripheral zones. The center of the rat's head was used to track time in zones, zone crossings, and total distance traveled. The apparatus was cleaned with an animal care disinfectant between all trials. Only six VPA rats were tested on this task because it was originally part of another task not reported here.</p> <hd id="AN0156930240-9">Water Maze (PND 39–49)</hd> <p>The water maze consisted of a circular tank filled with room temperature water made opaque with the addition of non-toxic paint. Prominent visual cues were affixed to the walls of the room housing the maze. A ceiling mounted camera enabled trials to be observed, recorded, and analyzed using Anymaze software. During the acquisition phase of the task, rats swam to a hidden Plexiglas platform submerged 1–2 cm below the water surface. For each trial, the rat was placed in the water facing the interior wall of the maze at one of four designated locations and then was given a maximum of 60 s to swim to the hidden platform. Rats failing to locate the platform were guided to it and placed on it for 10 s. Escape latencies (s) were measured for four trials within a daily session, for five consecutive days (20 trials total). During the recall phase of the task, memory of platform position was assessed by a probe test at 24 h and 72 h following the final session of the acquisition phase. During the probe tests the platform was removed and animals were allowed to explore the maze for 30 s. The time spent swimming in the quadrant that previously held the platform was used to measure recall of the original position of the submerged platform.</p> <hd id="AN0156930240-10">Operant Chamber Temporal Processing Tasks</hd> <p>Operant tasks were conducted on the 10 control rats and six VPA rats. We reduced the number of VPA rats for the operant tasks because of limited resources (both in terms of time and apparatus) for these tests.</p> <hd id="AN0156930240-11">Operant Chamber Apparatus</hd> <p>The temporal processing experiments were conducted using four standard operant chambers with retractable levers obtained from MED Associates (St. Albans, VT, USA) and controlled using Med-PC IV ® software, a PC, and a Med-PC interface located in an adjacent room. The interior of each chamber measured approximately 12 in wide, 8.25 in high, and 9.5 in deep and was in a sound attenuating cubicle. The front, back, and ceiling of the chambers were made of Plexiglas. The floor was made of thin metal bars running from the front to the back of the chamber positioned approximately 0.5 in apart. The right and left sides of the chambers were aluminum. The left side panel contained a house light in the top center of the wall and a tone generator in the top right that produced approximately 3000 Hz tones at approximately 75 dB. The right side panel contained two retractable levers, each approximately 2.5 in from the floor, 1 in from the wall, and 2 in apart. Directly between and below the levers was a food hopper opening that measured 2 in by 2 in and was 1 in from the floor. A pellet dispenser delivered 45-mg dustless precision purified-diet food pellets (BioServ, NJ, USA). A 1-in diameter lamp was located approximately 1.5 in above each lever. Ventilation fans mounted on the top of the right panel of the sound attenuating cubicles provided white noise.</p> <hd id="AN0156930240-12">General Lever Pressing Training</hd> <p>Lever pressing was shaped for all rats. They were then exposed to a fixed-ratio (FR) 1 schedule for 2 days. Individual trials occurred on both the left and right levers with 30 trials on the left and 30 trials on the right per session. Trial type was randomly selected without replacement from a list of five right- and five left-lever trials. The schedules were then changed to fixed interval (FI) 2, 4, and 8 s across three subsequent days.</p> <hd id="AN0156930240-13">Intertemporal Choice Task (PND 56–120)</hd> <p>The intertemporal choice task was a delay discounting procedure involving choices between a smaller-sooner reward (SSR) and a larger-later reward (LLR). In the task, the SSR option was always a signaled response-initiated fixed-interval (RIFI) 5-s schedule (see Fox &amp; Kyonka, [<reflink idref="bib42" id="ref64">42</reflink>], [<reflink idref="bib43" id="ref65">43</reflink>], [<reflink idref="bib44" id="ref66">44</reflink>]; Fox et al., [<reflink idref="bib47" id="ref67">47</reflink>]) resulting in the delivery of one food pellet, and the LLR option was a signaled-RIFI schedule with delays of 5, 15, and 30 s resulting in the delivery of two food pellets. The lever associated with the SSR option was counterbalanced across rats.</p> <p>For both the SSR and LLR options, a single response to the lever illuminated the corresponding light above it and retracted the unselected lever. After the delay elapsed, a single response was required to collect the food reward. During choice trials, both the SSR and LLR levers were available, but during forced-choice trials only one lever was available. Sessions lasted for 15 blocks. Each block consisted of two choice trials, one SSR forced-choice trial, and one LLR forced-choice trial. Sessions lasted for all 60 trials or 1 h, whichever occurred first. Across all rats, sessions timed out 36 times across seven rats (four control and three VPA). The intertrial interval (ITI) was always 30 s during which all lights were extinguished and levers retracted. LLR conditions lasted a minimum of 12 sessions in the SSR 5 s versus LLR 5 s condition, and then a minimum of six sessions in the subsequent two conditions, with no visual trends in the proportion of LLR choice across the final 3 to 5 sessions for each rat<emph>.</emph></p> <hd id="AN0156930240-14">Fixed-Interval Temporal Bisection Task (PND 181–200)</hd> <p>During training each rat was exposed to a fixed-interval (FI) 2 s schedule on the left lever and a FI 8 s schedule on the right lever during separate trials. On a trial, one lever was inserted into the chamber and a single press after the FI elapsed was required for food delivery. Trials occurred in blocks of 10, five FI 2 s and five FI 8 s trials randomly selected without replacement from a list, until a total of 60 trials occurred. This training took place for eight sessions.</p> <p>At the start of a trial during the experiment proper, the left and right levers were both inserted into the chamber. Each lever continued to be associated with same FI as in training. There were two types of trials that occurred: FI 2 s and FI 8 s trials, but both levers were always concurrently available during a trial. On FI 2 s trials, a food pellet was delivered contingent on a lever press to the FI 2 s lever after 2 s elapsed. On FI 8 s trials, a food pellet was delivered contingent on a lever press to the FI 8 s lever after 8 s elapsed. To be clear, food could only be earned on one lever per trial and the active lever was selected randomly without replacement from a list of six FI 2 s and six FI 8 s trials. The next trial followed immediately after food delivery. We also instituted a 3-s limited hold to earn food on both FIs: food could only be earned within 3 s of the active FI elapsing on a trial. If a response did not occur on the active lever within the limited hold, a 10-s blackout occurred during which the house light was extinguished and levers retracted. Trial type was not differentially signaled in any way other than the passage of time. Each session lasted for 36 short and 36 long trials, for 72 total trials.</p> <p>The dependent measure of interest in this task was when the animal switched from the short FI 2 s schedule to the long FI 8 s schedule on trials when food delivery was primed on the FI 8 s option. Therefore this test lasted for a minimum of 10 sessions and until there were no visual trends in the mean latency to the first FI 8 s lever press on FI 8 s trials across five consecutive sessions for each rat. The last three sessions were used for data analysis. For a diagram of the task see Fig. 2 (for an alternative visualization of the task, see Daniels et al. ([<reflink idref="bib29" id="ref68">29</reflink>])). The task is sometimes called the "switch-task," and is often employed to measure timing performance in humans and non-humans (Balci et al., [<reflink idref="bib12" id="ref69">12</reflink>]; e.g., Balci et al., [<reflink idref="bib11" id="ref70">11</reflink>]; Fox et al., [<reflink idref="bib45" id="ref71">45</reflink>]; Tosun et al., [<reflink idref="bib107" id="ref72">107</reflink>]).</p> <p>Graph: Fig. 2 Schematic of Fixed-Interval (FI) Bisection Task. The left panel shows a short trial, in which responding occurs and a reinforcer is earned on the short FI lever. The right panel shows a long trial, in which responding occurs on the short FI lever, but then the rat switches to the long FI lever, were responding occurs until the reinforcer is earned</p> <hd id="AN0156930240-15">Peak Procedure Timing Task (PND 201–224)</hd> <p>Only one lever was used in the peak procedure and it was associated with an FI 16 s schedule that functioned exactly like the FI schedules in the FI bisection task. At the start of a trial, the left lever was inserted into the chamber. The first press after 16 s resulted in lever retraction and food delivery. The next trial started 0.5 s after food delivery. Trials occurred in blocks of four food trials and one peak trial, randomly selected without replacement from a list. Food trials were as described, but peak trials lasted three times the FI (48 s) and did not end in food delivery. The lever was simply retracted and the subsequent trial followed. This test lasted for a minimum of 14 sessions with no trends in the mean latency to the first response on a trial for each rat. Peak trials from the last five sessions were used for analysis.</p> <hd id="AN0156930240-16">Elevated Plus-Maze (PND 230–232)</hd> <p>The elevated plus-maze was constructed of gray PVC plastic and consisted of two opposite open arms (50 × 10 cm), and two opposite arms enclosed with 40-cm high walls. A ceiling mounted camera enabled trials to be observed, recorded, and analyzed using Anymaze software. Rats were given two trials 24 h apart. For each trial, the rat was placed in the center of the maze facing one of the open arms and then allowed to freely explore the maze for 5 min. The apparatus was cleaned with an animal care disinfectant between all trials. Distance travelled as well as number and duration of entries into open vs enclosed arms were used as dependent measures.</p> <hd id="AN0156930240-17">Statistical Analyses</hd> <p>All behavioral tasks were analyzed using either two-way mixed ANOVA or Student's <emph>t</emph>-tests, except for the intertemporal choice, FI temporal bisection, and peak interval data, for which data analysis is explained below. Bonferroni corrections were applied to ANOVA post-hoc tests where appropriate.</p> <hd id="AN0156930240-18">Intertemporal Choice Data Analysis</hd> <p>We entered the weighted proportion LLR choice data for each rat into a generalized multilevel logistic regression (GLMR) model using the <emph>glmer</emph> function in the <emph>lme4</emph> package in the open access software <emph>R</emph> (R Core Team, [<reflink idref="bib94" id="ref73">94</reflink>]). Our final model included fixed effects of Group (Control and VPA) and LLR Delay (transformed to be LLR/SSR delay ratio) and random slopes for the LLR/SSR delay ratio and random intercepts for each subject. The categorical predictor of Group was effect coded.</p> <hd id="AN0156930240-19">FI Temporal Bisection Data Analysis</hd> <p>We plotted the data as the proportion of responding on the FI 8 s option in 0.1-s bins. This yielded a psychophysical timing function (see Fox et al., [<reflink idref="bib45" id="ref74">45</reflink>]). For a quantitative characterization of responding, we fit a sigmoid function (see Guilhardi &amp; Church, [<reflink idref="bib53" id="ref75">53</reflink>]) to the response gradients using the following equation: <emph>y</emph>(t) = <emph>a</emph>/(1 + (<emph>e</emph><sups><emph>−(t</emph>−<emph>c)</emph>)</sups>/<emph>b</emph>), where <emph>t</emph> is time, <emph>a</emph> determines the estimated maximum value of the function (i.e. the estimated asymptote), <emph>c</emph> determines the estimated center of the function (i.e. the "bisection point" or estimate of switch time), and <emph>b</emph> determines the estimated slope of the function (i.e. timing precision or an estimate of variability of switches). Smaller estimates of <emph>c</emph> indicate earlier switches from the short to long FI and faster subjective speed of time. Smaller estimates of <emph>b</emph> indicate steeper slopes and less variability in the time of the switch from the short to the long FI. We fit the sigmoid model using a multilevel non-linear regression approach in <emph>R</emph> (R Core Team, [<reflink idref="bib94" id="ref76">94</reflink>]), using the <emph>nlme</emph> library. For a similar approach, see Young ([<reflink idref="bib117" id="ref77">117</reflink>]). Group was coded as categorical and was a fixed effect predictor in the model. The <emph>a</emph>, <emph>b</emph>, and <emph>c</emph> parameters were random effects (fit at the group and individual level).</p> <hd id="AN0156930240-20">Peak Procedure Data Analysis</hd> <p>Responding on peak trials was the dependent measure of interest because we could measure when the animal starts responding in anticipation of food delivery and stops responding as anticipation wanes—hence we learn how accurately and precisely the animal anticipates when food will be delivered.</p> <p>For each individual trial, we fit a "low–high-low" model to the data (see Church et al. [<reflink idref="bib26" id="ref78">26</reflink>]; Fox &amp; Kyonka, [<reflink idref="bib44" id="ref79">44</reflink>]) using the following equation: <emph>A</emph> = <emph>t</emph><subs><emph>L1</emph></subs> (<emph>r</emph> – <emph>r</emph><subs><emph>L1</emph></subs>) + <emph>t</emph><subs><emph>H</emph></subs> (<emph>r</emph><subs><emph>H</emph></subs> – <emph>r</emph>) + <emph>t</emph><subs><emph>L2</emph></subs> (<emph>r</emph> – <emph>r</emph><subs><emph>L2</emph></subs>), where <emph>r</emph> was the overall mean response rate on a trial, <emph>r</emph><subs><emph>L1</emph></subs>, <emph>r</emph><subs><emph>H</emph></subs>, and <emph>r</emph><subs><emph>L2</emph></subs> were the response rates in the first low, the high, and the second low states, respectively, and <emph>t</emph><subs><emph>L1</emph></subs>, <emph>t</emph><subs><emph>H</emph></subs>, and <emph>t</emph><subs><emph>L2</emph></subs> were the durations of those respective states. The sum of the start time and half of the high-rate state duration was considered the middle time—the midpoint of the start and stop time on an individual trial—a measure of timing accuracy. We used this equation to calculate start and stop times that maximized the difference between the first and second low-rate states and the high-rate state between them. Trials in which the start time occurred after the programmed interval duration (i.e. 16 s), or the stop time occurred before the programmed interval duration (i.e. 16 s) were excluded from the analysis. The mean number of excluded trials per rat was 2.70 (<emph>SD</emph> 2.95) for the control group and 1.50 (<emph>SD</emph> 1.38) for the VPA group.</p> <p>We entered all of the obtained start, stop, and middle times from each trial for each rat separately into a multilevel linear regression model to compare groups. We used the <emph>lme4</emph> package and the <emph>lmer</emph> function in <emph>R</emph> (R Core Team, [<reflink idref="bib94" id="ref80">94</reflink>]). Group was the sole predictor variable and was coded as categorical. The model also included random intercepts for each subject.</p> <hd id="AN0156930240-21">Results</hd> <p>Developmentally, the VPA rats weighed less than the control animals at 8 weeks of age, but the difference was not statically significant (VPA, <emph>M</emph> = 286.5, <emph>SD</emph> 38.7; control, <emph>M</emph> = 296.4, <emph>SD</emph> 24.5). Three of 22 (13.6%) VPA animals had tail kinks, and none of the control rats did. No difference in weights and increased tail malformations is consistent with previously reported effects of in utero VPA exposure (Favre et al., [<reflink idref="bib40" id="ref81">40</reflink>]).</p> <hd id="AN0156930240-22">Rotarod</hd> <p>The analysis of latency to fall from the rotarod apparatus did not reveal a significant difference between control (<emph>M</emph> = 461.0 s, <emph>SD</emph> 137.9) and VPA animals (<emph>M</emph> = 497.5 s, <emph>SD</emph> 137.4), <emph>t</emph>(<reflink idref="bib30" id="ref82">30</reflink>) = 0.69, ns. These results suggest that gross motor behavior in the VPA animals was intact and the behavioral deficits observed in other tasks was likely not due to impaired motor coordination, strength, or endurance.</p> <hd id="AN0156930240-23">Y-Maze</hd> <p>General exploratory behavior in the Y-maze task was analyzed by comparing total distance traveled for both groups across both trials (Fig. 3, panel A). A two-way mixed factors ANOVA indicated no significant effect of trial type, but a significant effect of group, <emph>F</emph>(<reflink idref="bib1" id="ref83">1</reflink>, 30) = 7.28; <emph>p</emph> &lt; 0.05, η<subs>p</subs><sups>2</sups> =.195, and a significant group by trial interaction, <emph>F</emph>(<reflink idref="bib1" id="ref84">1</reflink>, 30) = 4.89; <emph>p</emph> &lt; 0.05, η<subs>p</subs><sups>2</sups> =.14.</p> <p>Graph: Fig. 3 Mean distance travelled (m) (A), mean percent time in the novel arm (B), and representative tracker plots (C) during the Y-maze test. Asterisks indicate difference at p &lt;.05. Error bars show standard error of the mean. Unlike the VPA group, control animals increased their distance travelled on the maze during trial 2. The VPA group spent less time in the trial 2 novel arm</p> <p>Post-hoc analysis found that the interaction was due to a significant difference in performance between the two groups during the second trial (<emph>p</emph> &lt; 0.01) that was not present during the first trial. Whereas the control group displayed a significant increase in total distance traveled between the first and second trial (<emph>p</emph> &lt; 0.01), the VPA group did not.</p> <p>Exploration of the novel arm presented on trial 2 indicated control animals spent a significantly higher percentage of their time in the novel arm compared to VPA, <emph>t</emph>(<reflink idref="bib30" id="ref85">30</reflink>) = 2.74, <emph>p</emph> &lt; 0.01, <emph>d</emph> = 1.09, Fig. 3, panel B. However, there was no significant difference between the groups in number of entries into the novel arm, <emph>t</emph>(<reflink idref="bib30" id="ref86">30</reflink>) = −.302, ns. Figure 3, panel C, shows representative tracker plots for the Y-maze task.</p> <hd id="AN0156930240-24">Activity Task</hd> <p>Analysis of locomotor activity in the activity box indicated VPA animals traveled a significantly shorter distance on the box floor compared to controls, <emph>t</emph>(<reflink idref="bib14" id="ref87">14</reflink>) = 4.08, <emph>p</emph> &lt; 0.01, <emph>d</emph> = 2.3, Fig. 4, panel A. VPA animals also displayed fewer grid line crossings compared to controls, <emph>t</emph>(<reflink idref="bib14" id="ref88">14</reflink>) = 3.88, <emph>p</emph> &lt; 0.01, <emph>d</emph> = 2.19, Fig. 4, panel B, and spent a larger proportion of trials in the corners of the box <emph>t</emph>(<reflink idref="bib14" id="ref89">14</reflink>) = -3.05, <emph>p</emph> &lt; 0.01, <emph>d</emph> = 1.76, Fig. 4 panel C. Figure 4, panel D, shows representative tracker plots for the activity box.</p> <p>Graph: Fig. 4 Mean distance travelled (m) (A), mean number of line crossings (B), mean percent time spent in the corner zones (C), and representative tracker plots (D) during the activity box test. Asterisks indicate difference at p &lt;.05. Error bars show standard error of the mean. The control group travelled further and had more zone crossings than the VPA group. VPA animals spent a larger portion of their time in the corner zones of the apparatus</p> <hd id="AN0156930240-25">Water Maze</hd> <p>Acquisition of the water maze task was analyzed by comparing the mean latencies to find the submerged platform for both groups across the five training days, Fig. 5, panel A. A two-way mixed factors ANOVA indicated significant main effects of group, <emph>F</emph>(<reflink idref="bib1" id="ref90">1</reflink>, 30) = 5.22; <emph>p</emph> &lt; 0.05, η<subs>p</subs><sups>2</sups> =.148, and training day, <emph>F</emph>(<reflink idref="bib4" id="ref91">4</reflink>, 120) = 89.6, η<subs>p</subs><sups>2</sups> =.738; <emph>p</emph> &lt; 0.001, but no significant group by training day interaction, <emph>F</emph>(<reflink idref="bib4" id="ref92">4</reflink>, 120) = 1.14; ns. The main effect of group is depicted in Fig. 5, panel B. Memory for the platform location was assessed through two separate 30 s probe trials (averaged together) where the submerged platform was removed from the apparatus, Fig. 5, panel C. There was no significant difference in the mean percent time each group spent in the target zone quadrant that previously held the submerged platform, <emph>t</emph>(<reflink idref="bib30" id="ref93">30</reflink>) = 0.591, ns. Figure 5, panel D, shows representative tracker plots for the water maze task. In sum, compared to control animals, the VPA rats generally located the submerged platform faster (Fig. 5, panel B) but did not show differences in memory. The lack of a memory effect is indicated by both the absence of a group by training day interaction during the acquisition phase of the task (Fig. 5, panel A) and the comparable performance of the VPA and control animals during the probe trials (Fig. 5, panel C).</p> <p>Graph: Fig. 5 Mean latency (s) to find the platform in the water maze test as a function of training day for each group (A) and aggregated across training day for each group (B). Mean percent time in target zone during probe trials for each group (C). Error bars show standard error of the mean. Representative tracker plots for the water maze task (D). Compared to control animals, the VPA rats generally located the submerged platform faster (B) but did not show differences in learning (A) or memory (C)</p> <hd id="AN0156930240-26">Intertemporal Choice Task</hd> <p>Figure 6 shows mean LLR choice proportions as a function of the LLR delay for both groups with the mean best fitting GLMR model overlaid as lines. The error bars are standard error of the mean. The GLMR model fitting revealed that LL/SS ratio (i.e. the LLR delay) was a significant predictor of choice behavior, β = − 1.19, <emph>SE</emph> = 0.09, <emph>z</emph> = − 12.82,<emph> p</emph> &lt;.001. Group, β = 0.67, <emph>SE</emph> = 0.49, <emph>z</emph> = 1.37,<emph> p</emph> =.17 and the Group x LL/SS ratio interaction, β = − 0.13, <emph>SE</emph> = 0.09, <emph>z</emph> = − 1.43,<emph> p</emph> =.15, were not significant predictors.</p> <p>Graph: Fig. 6 Mean proportion of larger-later (LL) choices during the intertemporal choice task as function of the LL delay (s). Error bars show standard error of the mean. Lines represent best-fitting model. See text for modeling details</p> <hd id="AN0156930240-27">FI Temporal Bisection</hd> <p>The multilevel non-linear (sigmoid) regression model revealed that group was not a significant predictor of the asymptote parameter, β = 0.03, <emph>SE</emph> = 0.03, <emph>t</emph> = 0.94,<emph> p</emph> =.34, the slope parameter, β = 0.01, <emph>SE</emph> = 0.01, <emph>t</emph> = 0.71,<emph> p</emph> =.48, or the midpoint ("bisection") parameter, β = − 0.04, <emph>SE</emph> = 0.03, <emph>t</emph> = − 1.09,<emph> p</emph> =.28. Figure 7 shows the mean proportion of FI 8 s ("long schedule") responding as a function of time during FI 8 s trials, with the mean best fitting sigmoid function overlaid. Although not statistically significant, the function is shifted leftward for the VPA rats, suggesting relatively faster subjective time perception. The VPA rats tended to switch from the FI 2 s schedule to the FI 8 s schedule sooner than the control rats during trials in which a reinforcer was available on the FI 8 s option.</p> <p>Graph: Fig. 7 Mean proportion of long responses (FI 8 s) as a function of time during the fixed-interval temporal bisection task. Best-fitting sigmoid models are overlaid as lines. See text for modeling details. The function for the VPA rats was shifted left of the control function—evidence of increased speed of time perception in the VPA model, though this difference was not statistically significant</p> <hd id="AN0156930240-28">Peak Procedure</hd> <p>Figure 8 shows mean start, middle, and stop times for rats in both groups. The models revealed that group was not significant predictor of start time, β = − 1.82, <emph>SE</emph> = 0.97, <emph>t</emph> = − 1.88, <emph>p</emph> =.08, or stop time, β = − 0.73, <emph>SE</emph> = 0.67, <emph>t</emph> = − 1.07, <emph>p</emph> =.30. However, group was a significant predictor of middle time (timing accuracy), with significantly earlier middle times for the VPA rats than the control rats, β = − 1.28, <emph>SE</emph> = 0.44, <emph>t</emph> = − 2.91, <emph>p</emph> =.01. Traditional <emph>t</emph>-tests were consistent with these results. High state durations, the duration between start and stop time (i.e. timing precision), were longer for the VPA rats (<emph>M</emph> = 14.92 s, <emph>SD</emph> 10.33) than control rats (<emph>M</emph> = 14.00 s, <emph>SD</emph> 4.24), though this difference was not significant, β = 1.08, <emph>SE</emph> = 1.43, <emph>t</emph> = 0.76, <emph>p</emph> =.46. Earlier middle times suggest increase speed of subjective time in the VPA rats—i.e. VPA rats were anticipating food sooner than control rats—consistent with earlier, but non-significant start times in this task and earlier switching in the FI temporal bisection task.</p> <p>Graph: Fig. 8 Mean start times (A), middle times (B), and stop times (C) during the peak interval timing task. Error bars show standard error of the mean. Asterisk indicates difference at p &lt;.05. Middle times were significantly earlier for the VPA rats—evidence of increased speed of time perception in the VPA model</p> <hd id="AN0156930240-29">Elevated Plus-Maze</hd> <p>Compared to the control group, we observed that VPA animals spent significantly less time on the maze grooming, <emph>t</emph>(<reflink idref="bib30" id="ref94">30</reflink>) = 1.82, <emph>p</emph> &lt; 0.05, <emph>d</emph> = 0.719, Fig. 9, panel A, and significantly more time in the enclosed arms, <emph>t</emph>(<reflink idref="bib30" id="ref95">30</reflink>) = − 2.06, <emph>p</emph> &lt; 0.05, <emph>d</emph> = − 0.88, Fig. 9, panel B. However, there were no significant differences between the groups in either the number of entries into the enclosed arms, <emph>t</emph>(<reflink idref="bib30" id="ref96">30</reflink>) = −.468, ns, or the total distance traveled on the maze, <emph>t</emph>(<reflink idref="bib30" id="ref97">30</reflink>) = − 1.15, ns. Figure 9, panel c, shows representative tracker plots for the elevated plus-maze task.</p> <p>Graph: Fig. 9 Mean grooming time (s) (A), mean time (s) in the enclosed arms (B), and representative tracker plots during the elevated plus maze. Error bars show standard error of the mean. Asterisks indicate difference at p &lt;.05. VPA rats spent less time grooming and more time in the enclosed arms—indications of increased anxiety-like behavior in the VPA model</p> <hd id="AN0156930240-30">Discussion</hd> <p>We successfully replicated many of the previously reported behavioral deficits in the VPA rat model of ASD, including increased anxiety-like behavior and Y-maze learning and memory abnormalities (e.g., Bambini-Junior et al., [<reflink idref="bib13" id="ref98">13</reflink>]; Banji et al., [<reflink idref="bib14" id="ref99">14</reflink>]; Favre et al., [<reflink idref="bib40" id="ref100">40</reflink>]; Fontes-Dutra et al., [<reflink idref="bib41" id="ref101">41</reflink>]; Kerr et al., [<reflink idref="bib63" id="ref102">63</reflink>]; Kim et al., [<reflink idref="bib67" id="ref103">67</reflink>]; Mabunga et al., [<reflink idref="bib76" id="ref104">76</reflink>]; Mychasiuk et al., [<reflink idref="bib89" id="ref105">89</reflink>]; Schneider &amp; Przewlocki, [<reflink idref="bib100" id="ref106">100</reflink>]; Schneider et al., [<reflink idref="bib102" id="ref107">102</reflink>]). While VPA model rats were generally quicker to locate the hidden platform during the acquisition of the water maze, their memory abilities assessed by the task did not significantly deviate from controls. The literature on the VPA model in the water maze is uneven. Some have reported VPA model deficits (Banji et al., [<reflink idref="bib14" id="ref108">14</reflink>]; Gao et al., [<reflink idref="bib51" id="ref109">51</reflink>]), but others have described a lack of deficit (Markram et al., [<reflink idref="bib82" id="ref110">82</reflink>]) or enhanced memory (Edalatmanesh et al., [<reflink idref="bib34" id="ref111">34</reflink>]). This variation may be related to differences in species, VPA delivery, and water maze protocols across the studies.</p> <p>In addition to the typical behavioral deficits known to be associated with the model, we found some evidence that VPA rats exhibited faster temporal processing compared to control animals. This effect of VPA exposure on timing is similar to a previously reported finding in mice (Acosta et al., [<reflink idref="bib1" id="ref112">1</reflink>]).</p> <p>Some previous work has reported no sex differences in general developmental trajectory in the VPA model (e.g., Favre et al., [<reflink idref="bib40" id="ref113">40</reflink>]). However, other researchers have reported sex differences in both behavioral and neuro-biological dependent variables (Anshu et al., [<reflink idref="bib10" id="ref114">10</reflink>]; Juybari et al., [<reflink idref="bib60" id="ref115">60</reflink>]; Kim et al., [<reflink idref="bib66" id="ref116">66</reflink>], [<reflink idref="bib65" id="ref117">65</reflink>]; Schneider et al., [<reflink idref="bib101" id="ref118">101</reflink>]). The issue of sex differences in the VPA model is an important one in terms of validity, given that human males are more likely to be diagnosed with ASD and present different symptomology compared to females (Schuck et al., [<reflink idref="bib103" id="ref119">103</reflink>]; Wilson et al., [<reflink idref="bib113" id="ref120">113</reflink>]). Given the limited sample we employed, we were unable to conduct meaningful comparisons between sexes and so analyzed only data from male subjects. Future research may be aimed at employing more rats with an explicit goal of evaluating timing differences between males and females in the VPA model.</p> <hd id="AN0156930240-31">General Conclusions and Future Research</hd> <p>The evidence for an impairment in interval timing in the human ASD population is somewhat mixed, but there is empirical (e.g., Allman et al., [<reflink idref="bib6" id="ref121">6</reflink>]; Isaksson et al., [<reflink idref="bib59" id="ref122">59</reflink>]) and anecdotal (e.g., Lawson, [<reflink idref="bib73" id="ref123">73</reflink>]) evidence that timing processes are disrupted and that these disruptions may underlie some of the core clinical symptoms associated with ASD (see Allman &amp; Falter, [<reflink idref="bib3" id="ref124">3</reflink>] for review). Consistent with some work with children diagnosed with ASD (Allman et al., [<reflink idref="bib6" id="ref125">6</reflink>]), we found evidence for increased speed of subjective time and possible reduced timing precision. Of particular interest is Allman et al. ([<reflink idref="bib6" id="ref126">6</reflink>]) finding that in a temporal bisection task (similar but not the same as the one used here), timing functions for children with ASD were shifted to the left as they were for our rats. Earlier middle times in the peak procedure that we observed are also consistent with this leftward shift in timing that they observed (i.e. faster subjective time). Allman et al. also found evidence of reduced timing precision in children, possibly consistent with the longer high-state durations we observed in the peak procedure for the VPA rats, though the difference was not statistically significant.</p> <p>There are reports on timing behavior in ASD human samples consistent and inconsistent with the Allman et al. ([<reflink idref="bib6" id="ref127">6</reflink>]) findings (see for review, Allman &amp; Meck, [<reflink idref="bib5" id="ref128">5</reflink>]; Allman et al., [<reflink idref="bib7" id="ref129">7</reflink>], [<reflink idref="bib8" id="ref130">8</reflink>]; Allman &amp; Falter, [<reflink idref="bib3" id="ref131">3</reflink>]). These discrepancies are probably exacerbated and made more difficult to interpret because of the vast heterogeneity in which ASD is manifest. Indeed, 20 individuals diagnosed with ASD may present with a host of different behavioral and cognitive abnormalities that range in severity. This range may extend from completely non-verbal and low functioning to verbal and near normal functioning. One advantage of using animal models to study ASD, and perhaps potential underlying deficits in temporal processing, is that this heterogeneity can be somewhat controlled for (note, though, that some heterogeneity in phenotype is appropriate for a valid model of ASD) and certain variables isolated in the lab. The VPA model is of high face and construct validity (e.g., Chomiak et al., [<reflink idref="bib23" id="ref132">23</reflink>], [<reflink idref="bib24" id="ref133">24</reflink>]; Favre et al., [<reflink idref="bib40" id="ref134">40</reflink>]), and there is now growing evidence of disrupted temporal processing in the model [that reported here and by Acosta et al. ([<reflink idref="bib1" id="ref135">1</reflink>])] that is consistent with reports in humans (e.g., Allman, [<reflink idref="bib2" id="ref136">2</reflink>]). More research is necessary to fully understand the possible scope of these findings. This work is made more difficult because temporal processing mechanisms in the brain are complex and diffuse and the teratogenic effects of VPA on brain development also appear diffuse and are not well understood (Ranger &amp; Ellenbroek, [<reflink idref="bib95" id="ref137">95</reflink>])—but there may be important consistencies to point out.</p> <p>At the neural systems level, the cerebellum and basal ganglia are commonly viewed as critical to timing behavior (Bares et al., [<reflink idref="bib15" id="ref138">15</reflink>]; Emmons et al., [<reflink idref="bib36" id="ref139">36</reflink>]; Petter et al., [<reflink idref="bib93" id="ref140">93</reflink>]; Sathyanesan et al., [<reflink idref="bib99" id="ref141">99</reflink>]) as are the associated neocortical regions that connect to and from them (Emmons et al., [<reflink idref="bib36" id="ref142">36</reflink>]; Meck, [<reflink idref="bib84" id="ref143">84</reflink>]; Narayanan et al., [<reflink idref="bib90" id="ref144">90</reflink>]). At the cellular level, plastic fluctuations between excitatory glutamatergic and inhibitory GABAergic signaling have been proposed as a fundamental neurochemical mechanism for timing (Buonomano, [<reflink idref="bib20" id="ref145">20</reflink>]; Motanis et al., [<reflink idref="bib87" id="ref146">87</reflink>]). Given the role of cortical-striatal circuitry, it is not surprising that the dopamine system has also been found to modulate temporal processing (Emmons et al., [<reflink idref="bib36" id="ref147">36</reflink>]; Heilbronner &amp; Meck, [<reflink idref="bib57" id="ref148">57</reflink>]; Malapani et al., [<reflink idref="bib80" id="ref149">80</reflink>]; Marinho et al., [<reflink idref="bib81" id="ref150">81</reflink>]; Meck, [<reflink idref="bib84" id="ref151">84</reflink>]; Narayanan et al., [<reflink idref="bib90" id="ref152">90</reflink>]; Soares et al., [<reflink idref="bib105" id="ref153">105</reflink>]). Serotonin and acetylcholine are yet other neurotransmitter systems linked to timing (Heilbronner &amp; Meck, [<reflink idref="bib57" id="ref154">57</reflink>]; Meck, [<reflink idref="bib85" id="ref155">85</reflink>]; Wittmann et al., [<reflink idref="bib115" id="ref156">115</reflink>]).</p> <p>Intriguingly, while the neurobiology of temporal processing is multifaceted, the neuroanatomical and neurochemical systems implicated in timing appear to be the same neural mechanisms disrupted in both human ASD and the VPA rodent model. For example, the cerebellum, basal ganglia, and neocortical areas projecting to them have been found to be disrupted in ASD (Becker &amp; Stoodley, [<reflink idref="bib17" id="ref157">17</reflink>]; Di Martino et al., [<reflink idref="bib32" id="ref158">32</reflink>]; Fatemi et al., [<reflink idref="bib39" id="ref159">39</reflink>]; Haznedar et al., [<reflink idref="bib56" id="ref160">56</reflink>]; Langen et al., [<reflink idref="bib71" id="ref161">71</reflink>]; Stoodley, [<reflink idref="bib106" id="ref162">106</reflink>]) and the VPA model (Gogolla et al., [<reflink idref="bib52" id="ref163">52</reflink>]; Kuo &amp; Liu, [<reflink idref="bib69" id="ref164">69</reflink>]; Lauber et al., [<reflink idref="bib72" id="ref165">72</reflink>]; Main &amp; Kulesza, [<reflink idref="bib79" id="ref166">79</reflink>]; Olexova et al., [<reflink idref="bib92" id="ref167">92</reflink>]; Wang et al., [<reflink idref="bib110" id="ref168">110</reflink>]). At the neurochemical level, the story is similar. The balance in glutamate-GABA signaling believed to be so critical for timing appears to be dysregulated in ASD (Nelson &amp; Valakh, [<reflink idref="bib91" id="ref169">91</reflink>]; Rubenstein &amp; Merzenich, [<reflink idref="bib98" id="ref170">98</reflink>]) and the VPA model (Fukuchi et al., [<reflink idref="bib49" id="ref171">49</reflink>]). Monoamine and cholinergic neurotransmitters linked to temporal processing are also reportedly disrupted in ASD (Friedman et al., [<reflink idref="bib48" id="ref172">48</reflink>]; Hamilton et al., [<reflink idref="bib55" id="ref173">55</reflink>]; Kemper &amp; Bauman, [<reflink idref="bib62" id="ref174">62</reflink>]; Muller et al., [<reflink idref="bib88" id="ref175">88</reflink>]) and the VPA model (Brumback et al., [<reflink idref="bib18" id="ref176">18</reflink>]; Kim et al., [<reflink idref="bib64" id="ref177">64</reflink>]; Wu et al., [<reflink idref="bib116" id="ref178">116</reflink>]).</p> <p>In sum, temporal processing appears to be a common functional link to the complex constellation of neuroanatomical and neurochemical disruptions observed in both human ASD and the VPA rodent model. These findings may be important for treating ASD because temporal processing underlies a host of important behavioral, social, and cognitive functions (Buhusi &amp; Meck, [<reflink idref="bib19" id="ref179">19</reflink>]). Indeed, behavior cannot escape time. Time is ubiquitous and processing of it is important for everyday functioning—especially when one considers the precise timing required to engage in regular social interactions that individuals with ASD so often struggle. Therefore, understanding and possibly treating these underlying temporal processing deficits in ASD has far reaching clinical implications. Instead of targeting a host of social behaviors in different contexts, training them up, and practicing them over and over to mastery, which may take months to years, it may be possible to target improvements in timing accuracy and precision that will generalize to a variety of behaviors and contexts. This may speed intervention effectiveness and generalizability, improving an individual's overall functioning much faster and with fewer resources.</p> <p>We are likely a ways off from fully understanding the potential for a "timing intervention" for ASD. There is much left to learn about possible distortions in time associated with ASD in humans and in non-human ASD models. For example, to what extent do timing abnormalities exist in the human ASD population? This remains unclear and future work is important for understanding the full scope of the possible problem and solution (Allman &amp; Falter, [<reflink idref="bib3" id="ref180">3</reflink>]). To what extent do timing abnormalities exist in other non-human models of ASD? Here we used the VPA model of ASD, but there are many other models of ASD that target other potential environmental, genetic, and neurobiological mechanisms of the disorder (e.g., Chadman et al., [<reflink idref="bib22" id="ref181">22</reflink>]; Ellenbroek et al., [<reflink idref="bib35" id="ref182">35</reflink>]; Ergaz et al., [<reflink idref="bib37" id="ref183">37</reflink>]; Gadad et al., [<reflink idref="bib50" id="ref184">50</reflink>]). Whether or not a timing deficit exists in these models is unknown.</p> <p>One limitation of the current study that should be addressed in future work was the imbalance in the control and VPA litters without culling the litters. This may have resulted in increased within-group variability, making differences between the VPA and control groups on the behavioral tasks more difficult to discern. We were also unable to run meaningful correlational analyses on behavior between tasks due to a limited sample size within each group on the timing tasks. Work that employs a litter-culling procedure and more animals may be able to address these limitations and better assess consistencies across and within timing and non-timing tasks. In addition, if a temporal processing deficit is found, certain pharmacological and environmental treatments may also be tested to see if they repair the deficit. In some cases, environmental enrichment (Schneider et al., [<reflink idref="bib102" id="ref185">102</reflink>]) or drugs (Chadman et al., [<reflink idref="bib22" id="ref186">22</reflink>]) have been shown to mitigate social and cognitive behavioral deficits associated with ASD. It would be interesting to see if these interventions likewise repair distortions in timing. Conversely, it would be worth investigating whether interventions aimed specifically at improving timing accuracy and precision, which could be as simple as repeated exposure to learning-to-time tasks, would also result in corresponding improvements in social behavior, repetitive behaviors, and anxiety-like behavior—some of the core clinical symptoms observed in humans.</p> <hd id="AN0156930240-32">Acknowledgments</hd> <p>The authors thank the following undergraduate students at St. Lawrence University for assistance with data collection, analysis, and presentation of results at scholarly conferences: Elina Breton, Rebecca Briggs, Meghan Demers-Peel, Laura Goldhar, Joe Licata, Emma Morgan, Alycia Nicholson, Sejla Palic, Joe Parise, Cole Poulin, Alea Robinson, Sumra Sikandar, Depika Singha, Emily Viehl, and Emma Visser. We also thank St. Lawrence University for funding this research.</p> <hd id="AN0156930240-33">Author contribution</hd> <p>Both authors contributed to the study conceptualization and design, interpretation of data, drafting the manuscript, and approval of the final manuscript. AEF collected and analyzed operant chamber task data. WED collected and analyzed the other behavioral task data.</p> <hd id="AN0156930240-34">Declarations</hd> <p></p> <hd id="AN0156930240-35">Conflict of interest</hd> <p>The authors declare no competing interests.</p> <hd id="AN0156930240-36">Publisher's Note</hd> <p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p> <ref id="AN0156930240-37"> <title> References </title> <blist> <bibl id="bib1" idref="ref53" type="bt">1</bibl> <bibtext> Acosta J, Campolongo MA, Höcht C, Depino AM, Golombek DA, Agostino PV. Deficits in temporal processing in mice prenatally exposed to valproic acid. 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| Items | – Name: Title Label: Title Group: Ti Data: Timing and Intertemporal Choice Behavior in the Valproic Acid Rat Model of Autism Spectrum Disorder – Name: Language Label: Language Group: Lang Data: English – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22DeCoteau%2C+William+E%2E%22">DeCoteau, William E.</searchLink><br /><searchLink fieldCode="AR" term="%22Fox%2C+Adam+E%2E%22">Fox, Adam E.</searchLink> (ORCID <externalLink term="http://orcid.org/0000-0001-8507-1008">0000-0001-8507-1008</externalLink>) – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="SO" term="%22Journal+of+Autism+and+Developmental+Disorders%22"><i>Journal of Autism and Developmental Disorders</i></searchLink>. Jun 2022 52(6):2414-2429. – Name: Avail Label: Availability Group: Avail Data: Springer. Available from: Springer Nature. One New York Plaza, Suite 4600, New York, NY 10004. Tel: 800-777-4643; Tel: 212-460-1500; Fax: 212-460-1700; e-mail: customerservice@springernature.com; Web site: https://link.springer.com/ – Name: PeerReviewed Label: Peer Reviewed Group: SrcInfo Data: Y – Name: Pages Label: Page Count Group: Src Data: 16 – Name: DatePubCY Label: Publication Date Group: Date Data: 2022 – Name: TypeDocument Label: Document Type Group: TypDoc Data: Journal Articles<br />Reports - Research – Name: Subject Label: Descriptors Group: Su Data: <searchLink fieldCode="DE" term="%22Autism%22">Autism</searchLink><br /><searchLink fieldCode="DE" term="%22Pervasive+Developmental+Disorders%22">Pervasive Developmental Disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Time+Perspective%22">Time Perspective</searchLink><br /><searchLink fieldCode="DE" term="%22Animals%22">Animals</searchLink><br /><searchLink fieldCode="DE" term="%22Motor+Reactions%22">Motor Reactions</searchLink><br /><searchLink fieldCode="DE" term="%22Intervals%22">Intervals</searchLink><br /><searchLink fieldCode="DE" term="%22Animal+Behavior%22">Animal Behavior</searchLink><br /><searchLink fieldCode="DE" term="%22Anxiety%22">Anxiety</searchLink><br /><searchLink fieldCode="DE" term="%22Memory%22">Memory</searchLink><br /><searchLink fieldCode="DE" term="%22Persistence%22">Persistence</searchLink> – Name: DOI Label: DOI Group: ID Data: 10.1007/s10803-021-05129-y – Name: ISSN Label: ISSN Group: ISSN Data: 0162-3257 – Name: Abstract Label: Abstract Group: Ab Data: Recently it has been proposed that impairments related to autism spectrum disorder (ASD) may reflect a more fundamental disruption in time perception. Here, we examined whether in utero exposure to valproic acid (VPA) can generate specific behavioral deficits related to ASD and time perception. Pups from control and VPA groups were tested using fixed-interval (FI) temporal bisection, peak interval, and intertemporal choice tasks. In addition, the rats were assessed on motor function, perseverative and exploratory behavior, anxiety, and memory. The VPA group displayed a leftward shift in timing functions. VPA rats displayed no deficits on the motor and memory tasks, but were significantly different from controls on measures of perseveration and anxiety. – Name: AbstractInfo Label: Abstractor Group: Ab Data: As Provided – Name: DateEntry Label: Entry Date Group: Date Data: 2022 – Name: AN Label: Accession Number Group: ID Data: EJ1335893 |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1007/s10803-021-05129-y Languages: – Text: English PhysicalDescription: Pagination: PageCount: 16 StartPage: 2414 Subjects: – SubjectFull: Autism Type: general – SubjectFull: Pervasive Developmental Disorders Type: general – SubjectFull: Time Perspective Type: general – SubjectFull: Animals Type: general – SubjectFull: Motor Reactions Type: general – SubjectFull: Intervals Type: general – SubjectFull: Animal Behavior Type: general – SubjectFull: Anxiety Type: general – SubjectFull: Memory Type: general – SubjectFull: Persistence Type: general Titles: – TitleFull: Timing and Intertemporal Choice Behavior in the Valproic Acid Rat Model of Autism Spectrum Disorder Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: DeCoteau, William E. – PersonEntity: Name: NameFull: Fox, Adam E. IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 06 Type: published Y: 2022 Identifiers: – Type: issn-print Value: 0162-3257 Numbering: – Type: volume Value: 52 – Type: issue Value: 6 Titles: – TitleFull: Journal of Autism and Developmental Disorders Type: main |
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