Name: the power of interstimulus interval for the assessment of temporal processing in rodents
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This work was supported in part by grants from NIH (National Institute on Drug Abuse, DA013137; National Institute of Child Health and Human Development HD043680; National Institute of Mental Health, MH106392; National Institute of Neurological Diseases and Stroke, NS100624) and the interdisciplinary research training program supported by the University of South Carolina Behavioral-Biomedical Interface Program. Dr. Landhing Moran is currently a Scientific Officer at the NIDA Center for Clinical Trials Network.

All animal protocols were reviewed and approved by the Animal Care and Use Committee at the University of South Carolina (federal assurance number: D16-00028).
1. Defining Parameters and Calibration of the Startle Apparatus
<ol>
	<li>Set up the startle response system (see Table of Materials) according to the manufacturer&#8217;s instructions.
	<ol>
		<li>Enclose the startle platform in a 10 cm-thick double-walled isolation cabinet.</li>
	</ol>
	</...

<ol>
	<li>Braff, D., Stone, C., Callaway, E., Geyer, M., Glick, I., Bali, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prestimulus+effects+on+human+startle+reflex+in+normals+and+schizophrenics.">Prestimulus effects on human startle reflex in normals and schizophrenics.</a> Psychophysiology. 15 (4), 339-343 (1978).</li><li>Castellanos, F. X., Fine, E. J., Kaysen, D., Marsh, W. L., Rapoport, J. L., Hallett, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sensorimotor+gating+in+boys+with+Tourette's+Syndrome+and+ADHD:+Preliminary+results.">Sensorimotor gating in boys with Tourette's Syndrome and ADHD: Preliminary results.</a> Biological Psychiatry. 39 (1), 33-41 (1996).</li><li>Moran, L. M., Booze, R. M., Mactutus, C. 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F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Progression+of+temporal+processing+deficits+in+the+HIV-1+transgenic+rat.">Progression of temporal processing deficits in the HIV-1 transgenic rat.</a> Scientific Reports. 6, 32831 (2016).</li><li>McLaurin, K. A., Booze, R. M., Mactutus, C. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Temporal+processing+demands+in+the+HIV-1+transgenic+rat:+Amodal+gating+and+implications+for+diagnostics.">Temporal processing demands in the HIV-1 transgenic rat: Amodal gating and implications for diagnostics.</a> International Journal of Developmenta Neuroscience. 57, 12-20 (2017).</li><li>Sechenov, I. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Reflexes of the Brain. , (1965).</li><li>Yerkes, R. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+sense+of+hearing+in+frogs.">The sense of hearing in frogs.</a> Journal of Comparative Neurology and Psychology. 15, 279-304 (1905).</li><li>Bowditch, H. P., Warren, J. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+knee-jerk+and+its+physiological+modifications.">The knee-jerk and its physiological modifications.</a> Journal of Physiology. 11, 25-64 (1890).</li><li>Cohen, L. H., Hilgard, E. R., Wendt, G. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sensitivity+to+light+in+a+case+of+hysterical+blindness+studied+by+reinforcement-inhibition+and+conditioning+methods.">Sensitivity to light in a case of hysterical blindness studied by reinforcement-inhibition and conditioning methods.</a> Yale Journal of Biology and Medicine. 6, 61-67 (1933).</li><li>Hoffman, H. S., Searle, J. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Acoustic+variables+in+the+modification+of+startle+reaction+in+the+rat.">Acoustic variables in the modification of startle reaction in the rat.</a> Journal of Comparative and Physiological Psychology. 60, 53-58 (1965).</li><li>Hoffman, H. S., March, R. R., Stein, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Persistence+of+background+acoustic+stimulation+in+controlling+startle.">Persistence of background acoustic stimulation in controlling startle.</a> Journal of Comparative and Physiological Psychology. 68 (2), 280-283 (1969).</li><li>Ison, J. R., Hammond, G. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Modification+of+the+startle+reflex+in+the+rat+by+changes+in+the+auditory+and+visual+environments.">Modification of the startle reflex in the rat by changes in the auditory and visual environments.</a> Journal of Comparative and Physiological Psychology. 75 (3), 435-452 (1971).</li><li>Moran, L. M., Hord, L. L., Booze, R. M., Harrod, S. B., Mactutus, C. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+role+of+sensory+modality+in+prepulse+inhibition:+An+ontogenetic+study.">The role of sensory modality in prepulse inhibition: An ontogenetic study.</a> Developmental Psychobiology. 58 (2), 211-222 (2016).</li><li>McLaurin, K. A., Booze, R. M., Mactutus, C. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evolution+of+the+HIV-1+transgenic+rat:+Utility+in+assessing+the+progression+of+HIV-1-associated+neurocognitive+disorders.">Evolution of the HIV-1 transgenic rat: Utility in assessing the progression of HIV-1-associated neurocognitive disorders.</a> Journal of Neurovirology. 24 (2), 229-245 (2018).</li><li>Hoffman, H. S., Ison, J. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reflex+modification+in+the+domain+of+startle:+I.+Some+empirical+findings+and+their+implications+for+how+the+nervous+system+processes+sensory+input.">Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system processes sensory input.</a> Psychological Review. 87 (2), 175-189 (1980).</li><li>Ison, J. R., Agrawal, P., Pak, J., Vaughn, W. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Changes+in+temporal+acuity+with+age+and+with+hearing+impairment+in+the+mouse:+A+study+of+the+acoustic+startle+reflex+and+its+inhibition+by+brief+decrements+in+noise+level.">Changes in temporal acuity with age and with hearing impairment in the mouse: A study of the acoustic startle reflex and its inhibition by brief decrements in noise level.</a> The Journal of the Acoustical Society of America. 104, 1696-1704 (1998).</li><li>. Startle response: Acoustic startle reflex response 101 Available from: <a target="_blank" href="https://mazeengineers.com/acoustic-startle-response/">https://mazeengineers.com/acoustic-startle-response/</a> (2014)</li><li>Curzon, P., Zhang, M., Radek, R. J., Fox, G. B., Buccafusco, J. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+behavioral+assessment+of+sensorimotor+processes+in+the+mouse:+Acoustic+startle,+sensory+gating,+locomotor+activity,+rotarod,+and+beam+walking.">The behavioral assessment of sensorimotor processes in the mouse: Acoustic startle, sensory gating, locomotor activity, rotarod, and beam walking.</a> Methods of behavior analysis in neuroscience. , (2009).</li><li>Geyer, M. A., Swerdlow, N. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Measurement+of+startle+response,+prepulse+inhibition,+and+habituation.">Measurement of startle response, prepulse inhibition, and habituation.</a> Current Protocols in Neuroscience. , (2001).</li><li>Parisi, T., Ison, J. 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The present protocol describes the power of varying ISI for the assessment of temporal processing for studies employing either cross-sectional or longitudinal experimental designs. Examining the effects of sensory modality, psychostimulant exposure, or age on the shape of the ISI function demonstrated its utility in revealing a differential sensitivity to the manipulation of ISI (i.e., shifts in the point of maximal inhibition) or a relative insensitivity to the manipulation of ISI (i.e., sharper inflec...

Temporal processing deficits have been implicated as a potential underlying neural mechanism for alterations in higher-level cognitive processes commonly observed in neurocognitive disorders. Prepulse inhibition (PPI) of the auditory startle response (ASR) is a translational experimental paradigm commonly used to examine temporal processing deficits, revealing profound alterations in neurocognitive disorders such as schizophrenia1, attention deficit hyperactivity disorder2 and HIV-1 associated neurocognitive disorders3,4. Specifically, assessments of temporal processing in preclinical models of HIV-1 have revealed the generality, relative permanence, and suggested the diagnostic utility of PPI across the majority of the animals&#39; functional lifespan3,4,5,6.
Use of an approach varying interstimulus interval (ISI; i.e., the time between the prepulse and the startle stimulus) in the analysis of reflex modification dates back to Sechenov in 18637. The seminal studies of reflex modification, a measure of sensorimotor gating, employed an approach varying ISI to assess flexor response and audition in frogs7,8, as well as knee-jerk responses in humans9. The first clinical application of the reflex modification procedure assessed visual sensitivity in a man with hysterical blindness10. Over a century after the first reports of reflex modification, the approach of varying ISI was popularized across a series of seminal papers11,12,13. Despite the inherent differences in the seminal studies on reflex modification (i.e., species, experimental procedures, reflexes), they established a temporal relationship that was strikingly similar between species.
Assessment of prepulse inhibition using an approach varying ISI, as detailed in the present protocol, has multiple advantages over the popularized percent of control approach. First, the approach affords an opportunity to establish the shape of the ISI function, including increases (sharper curve inflections) or decreases (flattening of the response amplitude curve)3,15 in startle amplitude, as well as shifts in the peak point of response inhibition3,5. Additionally, when an approach varying ISI is employed, startle response is a relatively stable phenomenon1, suggesting the potential utility of the approach in longitudinal studies examining the progression of neurocognitive deficits5,15. Finally, PPI provides a critical opportunity to understand the underlying neural circuitry involved in neurocognitive disorders16.
In our study, we employed two experimental paradigms (Figure 1), including cross-modal PPI and gap prepulse inhibition (gap-PPI), to evaluate the utility of an approach varying ISI to delineate effects of sensory modality, psychostimulant exposure, and age. The cross-modal PPI experimental paradigm utilizes the presentation of an added stimulus (e.g., tone, light, air puff) as a discrete prestimulus prior to an acoustic startling stimulus. In sharp contrast, in the gap-PPI experimental paradigm, the absence of a background (e.g., removal of background noise, light, or air puff) serves as a discrete prestimulus. Here, we describe both experimental paradigms for the assessment of temporal processing, as well as statistical approaches for the analysis of PPI and gap-PPI. Within the discussion, we compared the conclusions one would draw from the variable ISI approach and the popularized percent of control approach.

<table>
	<tbody>
		<tr>
			<td>SR-Lab Startle Response System</td>
			<td>San Diego Instruments</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Isolation Cabinet</td>
			<td>Industrial Acoustic Company</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>SR-Lab Startle Calibration System</td>
			<td>San Diego Instruments</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>High-Frequency Loudspeaker</td>
			<td>Radio Shack</td>
			<td>model #40-1278B</td>
			<td></td>
		</tr>
		<tr>
			<td>Sound Level Meter</td>
			<td>Bruel &#38; Kjaer</td>
			<td>model #2203</td>
			<td></td>
		</tr>
		<tr>
			<td>Perspex Cylinder</td>
			<td>San Diego Instruments</td>
			<td></td>
			<td>Included with the SR-Lab Startle Response System</td>
		</tr>
		<tr>
			<td>SR-Lab Startle Response System Software</td>
			<td>San Diego Instruments</td>
			<td></td>
			<td>Included with the SR-Lab Startle Response System</td>
		</tr>
		<tr>
			<td>Light Meter</td>
			<td>Sper Scientific, Ltd.</td>
			<td>model #840006</td>
			<td></td>
		</tr>
		<tr>
			<td>Airline Regulator</td>
			<td>Craftsman</td>
			<td>model #16023</td>
			<td></td>
		</tr>
		<tr>
			<td>SPSS Statistics 24</td>
			<td>IBM</td>
			<td></td>
			<td>Used for Statistical Analyses (Optional)</td>
		</tr>
	</tbody>
</table>

the power of interstimulus interval for the assessment of temporal processing in rodents

Temporal processing deficits have been implicated as a potential elemental dimension of higher-level cognitive processes, commonly observed in neurocognitive disorders. Despite the popularization of prepulse inhibition (PPI) in recent years, many current protocols promote using a percent of control measure, thereby precluding the assessment of temporal processing. The present study used cross-modal PPI and gap prepulse inhibition (gap-PPI) to demonstrate the benefits of employing a range of interstimulus intervals (ISIs) to delineate effects of sensory modality, psychostimulant exposure, and age. Assessment of sensory modality, psychostimulant exposure, and age reveals the utility of an approach varying the interstimulus interval (ISI) to establish the shape of the ISI function, including increases (sharper curve inflections) or decreases (flattening of the response amplitude curve) in startle amplitude. Additionally, shifts in peak response inhibition, suggestive of a differential sensitivity to the manipulation of ISI, are often revealed. Thus, the systematic manipulation of ISI affords a critical opportunity to evaluate temporal processing, which may reveal the underlying neural mechanisms involved in neurocognitive disorders.

A prominent non-monotonic ISI function was observed in cross-modal PPI (Figures 2A, 3A, 4A) and gap-PPI (Figures 2B, 3B, 4B). Baseline startle responses were observed at the 0 and 4000 ms ISIs, included as reference trials within a test session. The importance of the 4000 ms ISI cannot be understated, as it most closely resembles the PPI test trials (i.e., 30, 50, 100, 200 ms ISIs) in that the subject receives both the prepulse and startling stim...

Watch this Scientific Journal Video about The Power of Interstimulus Interval for the Assessment of Temporal Processing in Rodents at JoVE.com

The Power of Interstimulus Interval for the Assessment of Temporal Processing in Rodents

Temporal processing, a preattentive process, may underlie deficits in higher-level cognitive processes, including attention, commonly observed in neurocognitive disorders. Using prepulse inhibition as an exemplar paradigm, we present a protocol for manipulating interstimulus interval (ISI) to establish the shape of the ISI function to provide an assessment of temporal processing.

Temporal processing deficits have been implicated as a potential elemental dimension of higher-level cognitive processes, commonly observed in ...

This method can help answer key questions in the field of neuroscience by characterizing neurocognitive disorders and their progression across the lifespan via cross-sectional and longitudinal assessments. The main advantage of this technique is that it utilizes the systematic manipulation of ISI to afford a critical opportunity for the evaluation of a temporal processing. The implications of this technique extend for the assessment of neurocircuitry alterations in neurocognitive disorders, because the serial neural circuit mediating PPI has been well-established.To begin this procedure, open the Startle Response system software, define a pulse-only ASR trial by selecting Definitions, then Define Trial. Type a trial name, hit enter, and Record Data. Set the Analog Level to 720.Define the Wait Length as 20 milliseconds, and introduce Background. End the trial and hit Accept to save it. To create a 30-milliseconds trial definition for acoustic PPI, select Definitions, then Define Trial.Type a trial name and hit enter. Set the Analog Level to 600 at zero millisecond to introduce the pre-stimulus. Assign the Wait Length to 20 milliseconds to specify the length of the pre-stimulus.Then, set the Analog Level to 440 at 20 milliseconds to remove the pre-stimulus. Define the Wait Length dependent upon ISI, and specify Record Data. Set the Analog Level to 720 and assign the Wait Length to 20 milliseconds.Next, introduce Background, then end the trial and hit Accept to save the trial. Afterward, create a 30-milliseconds definition for acoustic gap PPI. Selection Definitions, one, Define Trial.Type a trial name and hit enter. Set the Analog Level to zero at zero millisecond to introduce the pre-stimulus. Assign the Wait Length to 20 milliseconds to specify the length of the pre-stimulus.Then, set the Analog Level to 440 at 20 milliseconds to remove the pre-stimulus. Subsequently, define the Wait Length dependent upon ISI, then specify Record Data. Set the Analog Level to 720.Assign the Wait Length to 20 milliseconds, and introduce Background. End the trial, hit Accept to save the trial. To create a habituation session, select Definitions and Define Session.Set the number of Record Samples to 200, the Samples per Second to 2, 000, the Background analog level to 440, the Acclimation Period to 5 minutes, and the sequence Repetitions to 36. Type 10 into the ITI List box. Next, click Add, and select the Pulse Only ASR trial.Click Save to save the Habituation session. Subsequently, define the session for cross-modal PPI by selecting Definitions and Define Session. Set the number of Record Samples to 200, the Samples per Second to 2, 000, the Acclimation Period to five minutes, the Background analog level to 440, and the sequence Repetitions to one.Then, define the ITI list by typing 10 into the first five ITI List boxes. Type the ITI values into the next 72 ITI list boxes, representing trials with a pre-stimulus. Afterward, click Add, select the Pulse Only ASR trial, and load it six times for trials one to six.Load the six-trial blocks in an A-B-B-A counterbalanced order of presentation for a cross-modal PPI. Then, click Save to save the session. Next, define the session for gap PPI by selecting Definitions and Define Session.Set the number of Record Samples to 200, the Samples per Second to 2, 000, the Acclimation Period to five minutes, the Background analog level to 440, and the sequence Repetitions to one. To define the ITI list, type 10 into the first five ITI List boxes. Type the ITI values into the next 72 ITI List boxes, representing trials with a pre-stimulus.Then, select the Pulse Only ASR trial and add it six times for trials one to six. Create six trial blocks for each pre-stimulus modality using a Latin square design and save the session. In this procedure, handle the animals to allow for acclimation across a series of days prior to beginning experimentation.Open the Startle Response system software. Click Run and select the session of interest. Then, input an Output File Name and click OK.Enter Subject, Group, and ID information and click Continue.Place the animal into the startle apparatus, using an animal enclosure that is most appropriate for the size of the animal. Click OK to begin the session. When it is done, export data for analysis by clicking Reports, then, Concatenate Data.Load the data file and click Add. Then, click ASCII to save the data output. The utility of an approach varying the ISI to delineate effects of sensory modality and cross-modal PPI are illustrated here.A prominent shift in the point of maximal inhibition is dependent upon sensory modality, suggesting a differential sensitivity to the manipulation of ISI. Specifically, maximal inhibition is observed at the 30-milliseconds ISI following the presentation of a discrete acoustic pre-stimulus at the 50-milliseconds ISI following the presentation of a discrete visual pre-stimulus and at the 200-milliseconds ISI following the presentation of a discrete tactile pre-stimulus. Following an animal's experience with each pre-stimulus in cross-modal PPI, the generalizability of sensory modality effects was assessed in gap PPI.This figure demonstrates the generalizability of varying the ISI to delineate effects of sensory modality. A prominent shift in the point of maximal inhibition suggesting a differential sensitivity to the manipulation of ISI was observed in tactile gap PPI relative to acoustic gap PPI and visual gap PPI. The utility of an approach varying the ISI to delineate effects of psychostimulant in cross-modal PPI are illustrated here.At the post-test assessment, most notably, a relative flattening of the ISI function is observed, suggesting a relative insensitivity to the manipulation of ISI relative to the pre-test assessment. Additionally, a prominent shift in the point of maximal inhibition is also revealed, supporting a differential sensitivity to the manipulation of ISI. Specifically, maximal inhibition is observed at the 30-millisecond ISI during the pre-test assessment and at the 100-millisecond ISI during the post-test assessment.Subsequently, the generalizability of the varying ISI approach to delineate effects of psychostimulant exposure was assessed in auditory gap PPI. A significantly flatter ISI function was observed at the post-test assessment relative to the pre-test assessment, suggesting a relative insensitivity to the manipulation of ISI. The development of temporal processing can be assessed using a longitudinal experimental design.The development of temporal processing in visual PPI is illustrated here. The point of maximal inhibition at all ages is at the 50-millisecond ISI, however, a sharper inflection of the ISI function is observed across age, suggesting a perceptual sharpening which occurs with development. Subsequently, the generalizability of the varying ISI approach to examine the development of temporal processing was assessed in auditory gap PPI.At post-natal day 30, an insensitivity to the manipulation of ISI was observed, evidenced by a flatter ISI function relative to PD90 or PD150. While attempting this procedure, it's important to implement critical experimental design considerations, including a Latin square experimental design for the presentation of ISIs, two control trials including the zero and 4, 000-millisecond ISI and a variable ITI. Following this procedure, other neurocognitive assessments including a signal-detection operant task and neuroanatomical assessments can be performed to further assess temporal processing deficits and their underlying neural mechanisms.

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The use of a craniotomy for in vivo experiments provides an opportunity to investigate the dynamics of diverse cellular processes in the mammalian brain ...

Assessment of Hippocampal Dendritic Complexity in Aged Mice Using the Golgi-Cox Method

Dendritic spines are the protuberances from the neuronal dendritic shafts that contain&#160; excitatory synapses. The morphological and branching ...

Measurement &amp; Analysis of the Temporal Discrimination Threshold Applied to Cervical Dystonia

Measurement & Analysis of the Temporal Discrimination Threshold Applied to Cervical Dystonia

The temporal discrimination threshold (TDT) is the shortest time interval at which an observer can discriminate two sequential stimuli as being ...

Cannula Implantation into the Cisterna Magna of Rodents

Cisterna magna cannulation (CMc) is a straightforward procedure that enables direct access to the cerebrospinal fluid (CSF) without operative damage to ...

Operant Protocols for Assessing the Cost-benefit Analysis During Reinforced Decision Making by Rodents

Reinforcement-guided decision making is the ability to choose between competing courses of action based on the relative value of the benefits and their ...