98th Meeting of the German Physiological Society // Joint Meeting with the Austrian Physiological Society (APS) and Life Sciences Switzerland (LS2) Physiology
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Circuit Neurophysiology

Chair(s): M. Bartos (Freiburg, Germany); A. Draguhn (Heidelberg, Germany)
 
Shortcut: B 01
Date: Tuesday, 1 October 2019, 5:00 p.m.
Room: Poster Area (Building N27)
Session type: Poster Session

Contents

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B 01-1

Effects of activin A on hippocampal network activity (#277)

M. Dahlmanns1, J. K. Dahlmanns2, F. Zheng1, C. Alzheimer1

1 University of Erlangen-Nürnberg, Institute of Physiology and Pathophysiology, Erlangen, Germany
2 University Hospital Erlangen, University Hospital Erlangen, Erlangen, Germany

In addition to its established role in neurodevelopment and neuroprotection, the TGF-β family member activin A is increasingly recognized as a modulator of synaptic transmission, cognitive functions and affective behavior. Here, we explored how activin affects oscillations and spike routing within hippocampal networks using slice and culture preparations.

Transverse hippocampal slices (400 µm thick) were prepared from wt mice and mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB), which disrupts activin signaling. Hippocampal oscillations were induced by the cholinergic agonist carbachol (25 µM) and monitored by means of field potential recordings in CA1 stratum oriens and CA3 stratum radiatum. Superfusion of slices with carbachol induced robust oscillations in the low theta range in both regions of wt slices, whereas no such drug effect was observed in dnActRIB slices. Only at a higher carbachol concentration (37.5 µM), theta oscillations emerged also in the mutant preparation, suggesting that endogenous activin signaling serves to promote cholinergically driven theta activity.

The impact of activin on spike routing was explored in dissociated primary hippocampus cultures, in which network activity was monitored with the calcium fluorescent dye Fluo-8AM. Based on the calcium responses of electrically-activated neurons, spiking was detected and the functional network was reconstructed. In cultures incubated with activin A (25ng/ml for 48 h) we found no alterations in the synchrony of the cells. An analysis of the functional network properties however showed, that activin A although not changing the overall connectivity degree, had a number of significant effects on parameters of signal transmission and routing: an increase in network strength, a decline in the characteristic path length, and an increase in network assortativity. When computationally removing individual cells from the network, activin A-treated networks displayed a lower vulnerability than control networks, reflecting an increased reliability of information transfer.

Our study is the first to interrogate the impact of activin on functional network connectivity. We found that disruption of activin signaling impairs the appearance of theta oscillations, whereas a rise in activin, as observed during behaviourally relevant stimuli, fosters a number of features that are expected to augment the performance of the network.

Keywords: activin A, synaptic plasticity, hippocampus
B 01-2

Impaired Processing of Self-Generated Sounds in a Mouse Model of Schizophrenia Predisposition (#294)

B. P. Rummell1, J. A. Gogos2, 3, T. Sigurdsson1

1 Goethe University Frankfurt, Institute of Neurophysiology, Frankfurt am Main, Germany
2 Columbia University, Department of Physiology and Cellular Biophysics, New York, New York, United States of America
3 Columbia University, Department of Neuroscience, New York, New York, United States of America

Studies in humans and animal models have consistently shown that auditory responses to sounds caused by self-generated actions are attenuated. In contrast, patients suffering from schizophrenia show reduced attenuation of such sounds. However, the causes of this sensory processing deficit in schizophrenia are not well understood. To address this, we examined neural responses to self-generated sounds in Df(16)A+/- mice, which model the strongest known genetic risk factor for schizophrenia, the 22q11.2 microdeletion. Df(16)A+/- mice (n=9) and their wild-type (WT) littermates (n=9) were trained to press a lever which triggered a sound, while the identical sound was also randomly delivered independent of the animal’s behavior. During this task, responses of auditory cortex (Actx) neurons to these sounds were recorded using silicon probes. In WT animals, responses of Actx neurons to self-generated sounds were robustly attenuated in amplitude, compared to randomly occurring stimuli. In contrast, responses of neurons in Df(16)A+/- mice show reduced attenuation compared to WT littermates. No differences were found in responses to random sounds between genotypes and we observed that general movement related attenuation of auditory sounds to be similar between genotypes. Interestingly, we found neural activity that preceded the self-generated sound to be specifically significantly reduced in putative interneurons in Df(16)A+/- animals suggesting anticipatory movement-related activity. These findings demonstrate that the 22q11.2 microdeletion, a major risk factor for schizophrenia, causes impaired attenuation of self-generated sounds similarly to what is found in patients, and reveal a possible cellular basis for this sensory deficit.

Keywords: auditory cortex, corollary discharge, schizophrenia
B 01-3

Caloric restriction improves in vivo cortical function in aged mice (#88)

N. Asavapanumas1, N. Fröhlich1, C. Lerdkrai1, E. Zirdum1, O. Garaschuk1

1 Eberhard Karls University of Tübingen, Institute of Physiology, Department of Neurophysiology, Tübingen, Baden-Württemberg, Germany

Aging is accompanied by an increasing risk of developing cognitive impairment, including learning and memory deficits. Caloric restriction (CR) is known to extend the life expectancy, delay the onset of aging-related disorders and to enhance the cognitive function. Here we monitored the animal’s body status between 3 and 18 months of age and characterized the functional in vivo properties of cortical neurons during normal aging or under CR. During aging of ad libitum fed mice we observed an increased body weight by 23.1% associated with a mortality of 33.3%. In vivo two-photon Ca2+ imaging revealed a significant aging-mediated increase in the frequency of spontaneous Ca2+ transients in layer 2/3 neurons of the frontal/motor and the primary visual cortex. Interestingly, the aging-related hyperactivity developed earlier in the frontal/motor compared to the visual cortex. Moreover, aging-related increase in neuronal hyperactivity was accompanied by an impairment of visual processing, i.e. a significant decrease in the orientation and to a lesser extent in the direction selectivity. In aged (18-month-old) mice the two-choice visual discrimination test and the object recognition test revealed a significant reduction of (i) both pattern detection and discrimination abilities as well as (ii) the ability to remember the familiar object, indicative of deficits in cognition and memory performance. A reduction of the daily food intake by 30% for 12 months (CR) led to a decrease of the body weight by 16.1% and to a decline of the mortality (6.4%). CR counteracted the hyperactivity of cortical neurons and partially ameliorated the deficits in visual processing by causing a significant improvement of the orientation selectivity. Consistently, CR significantly improved both pattern detection and discrimination abilities of aged mice as well as their memory performance in the novel object recognition text to the levels observed in young 3-month-old mice.

Taken together, normal aging is accompanied by (i) an increased body weight, (ii) region-specific development of the hyperactivity of cortical neurons, (iii) impairment of visual processing as well as (iv) the aging-related deterioration of cognition. CR significantly reduces neuronal hyperactivity and ameliorates the observed deficits in cognitive abilities of aged mice.

B 01-4

Non-canonical axon morphologies gate information flow in neuronal ensembles. (#245)

A. Hodapp1, M. E. Kaiser1, M. Klumpp1, A. Draguhn1, Y. Yanovsky1, M. Engelhardt2, C. Thome1, M. Both1

1 Heidelberg University, Institute of Physiology and Pathophysiology, Heidelberg, Baden-Württemberg, Germany
2 Heidelberg University, Institute of Neuroanatomy, Medical Faculty Mannheim, Mannheim, Baden-Württemberg, Germany

Neurons receive multiple synaptic inputs at their dendrites, which integrate within the somato-dendritic compartment and generate action potentials (AP) once voltage threshold is reached at the axon initial segment. Canonically, the axon of pyramidal cells is located next to the soma but we have recently shown that in about 50% of CA1 pyramidal cells the axon originates from a basal dendrite rather than from the soma. This axon-carrying dendrite (AcD) might constitute a privileged input channel in this subset of cells. Additionally, previous work in vitro has shown that during sharp wave-ripple complexes (SPW-R) CA1 pyramidal cells are recruited in a peculiar way: their somatic action potential initiates abruptly from baseline resembling an ectopically generated spike. Here we asked whether the anatomical feature of AcD cells underlies the selective activation of CA1 pyramidal cells during SPW-R.

To test our hypothesis, we performed extra- and intracellular electrophysiological recordings as well as immunofluorescent staining in acute hippocampal mouse brain slices. Interestingly, excitatory input to axon-carrying dendrites remains efficient even during the strong perisomatic inhibition that accompanies SPW-Rs and prevents other pyramidal cells from firing. Thus, only AcD cells are able to fire APs during the events. In line with our previous data, AP waveforms resemble ectopically generated spikes. Multicompartment modelling of single cells confirms that in somatic recordings of AcD cells, APs initiate abruptly from resting membrane potential when excitatory and inhibitory inputs arrive with a certain spatio-temporal configuration. Intracellular administration of picrotoxin diminished perisomatic inhibition, recruited more cells into SPW-R and shifted ectopic AP waveforms towards classical APs.

In summary, AcD cells are selectively recruited during SPW-R activity while the firing probability of other neurons is controlled by perisomatic inhibition. As a result, reducing GABAergic input can modify ensemble composition within short time. Our findings suggest that perisomatic inhibition combined with different axon origins provide a mechanism to rapidly gate and route incoming information and thus enables fast modifications of ensemble compositions.

Keywords: network oscillations, hippocampus, perisomatic inhibition
B 01-5

Stable behavioral state-specific mesoscale activity patterns in the developing cortex of neonates (#109)

N. Mojtahedi1, Y. Kovalchuk1, A. Böttcher2, O. Garaschuk1

1 Eberhard Karls University of Tübingen, Institute of Physiology, Department of Neurophysiology, Tübingen, Baden-Württemberg, Germany
2 Eberhard Karls University of Tübingen, Werner Reichardt Centre for Integrative Neuroscience, Tübingen, Baden-Württemberg, Germany

Endogenous neuronal activity is a hallmark of the developing brain. In rodents, a handful of such activities were described in different cortical areas but the unifying macroscopic perspective is still lacking. Here we combined large-scale in vivo Ca2+ imaging of the dorsal cortex in awake neonatal mice with advanced mathematical analyses to reveal unique behavioral state-specific maps of endogenous activity. These maps were remarkably stable over time within and across experiments and used patches of correlated activity with little hemispheric symmetry as well as stationary and propagating waves as building blocks. Importantly, the maps recorded during motion and rest were almost inverse, with sensory-motor areas active during motion and posterior-lateral areas active at rest. The retrosplenial cortex engaged in both resting- and motion-related activities, building functional long-range connections with respective cortical areas. Together, these data provide an unprecedentedly complete view on the endogenous network activity and set the stage for future inactivation studies probing its exact function in orchestrating the early development of the mammalian brain.

Keywords: endogenous network activity, large-scale in vivo Ca2+ imaging, state-specific activity maps
B 01-6

Amplitudes and propagation of cortical spreading depolarization (CSD) in adult rats are influenced by Calcitonin gene-related peptide (CGRP) (#84)

F. Gimeno-Ferrer1, F. Richter1, R. Bauer2, A. Lehmenkühler3, H. - G. Schaible1

1 University Hospital Jena , Institute of Physiology I / Neurophysiology, Jena, Thuringia, Germany
2 University Hospital Jena, Institute of Molecular Cell Biology, CMB-Center for Molecular Biomedicine, Jena, Thuringia, Germany
3 Pain Institute & Center for Medical Education, Düsseldorf, North Rhine-Westphalia, Germany

It is known from the literature that CGRP plays an important role in migraine and antagonizing CGRP is an effective preventing treatment against migraine pain. CGRP is able to increase neuronal excitability. Further it has been shown that a CSD - that is known to be the correlate of the migraine aura - can release CGRP in rat neocortical slices. Whether CGRP enhances brain’s susceptibility for CSD or influence CSD itself in vivo has not been investigated yet. To test this, we applied CGRP at different concentrations topically to a restricted part of the cortical surface and compared the electrocorticogram, regional cerebral blood flow (rCBF) and parameters of CSD in the treated region with the untreated brain area.

In spontaneously breathing anesthetized adult rats (sodium thiopentone, 100 mg/kg, i.p.) CSDs were recorded in cerebral cortex with two pairs of glass micropipettes (distance 5-6 mm) at depths of 400 and 1200 µm in two areas of the cortex, separated by a wall. In addition, in the treated area CSD-related changes in extracellular potassium concentration ([K+]e) were measured with a micropipette filled with Corning IE-190 ionic exchanger. In the untreated area, CSD was elicited by a microinjection of 1 M KCl (100 kPa, 300 ms up to 1 s, depth 1200 µm) into the grey matter at intervals of 30 min. In the remote area 100 µl of CGRP at concentrations from 10-8 M to 10-5 M (only one concentration per experiment) were applied topically and left there for three hours. In both cortical areas rCBF was measured.

In all rats tested, a pulse of KCl elicited a single propagating CSD. The topical application of CGRP to the brain surface reduced the amplitudes of CSD in the treated area (10-5 M to 60 % of controls; 10-8 M to 70 % of controls; untreated to 85-90 % of controls) and slowed the propagation velocity (10-5 M from 3.0 to 2.6 cm/s; 10-8 M from 2.4 to 2.2 cm/s). Rarely spontaneous CSD were observed originating from the CGRP-treated area. In another few rats, CGRP induced focal ictal activity after 2-3 hours of application that did not spread into the untreated cortex. Focal ictal activity occurred at intervals of 8-10 min and was accompanied by transient increases in [K+]e. However, so far neither the ignition of CSDs nor the induction of focal ictal activity showed a dose-dependency to CGRP.

Our results identify the neuropeptide CGRP as a candidate that could interfere with CSD by changing neuronal excitability.

Keywords: spreading depolarization, electrocorticogram, neuropeptide
B 01-7

The contribution of medial prefrontal cortex neurons to spatial working memory (#355)

P. Vogel1, S. Duvarci1, T. Sigurdsson1

1 Goethe University Frankfurt, Institute of Neurophysiology, Frankfurt, Germany

Spatial working memory (SWM), the ability to store and update spatial information in the short term, is an essential feature of goal-directed behavior. Lesion and inactivation studies suggest that the medial prefrontal cortex (mPFC) plays a key role in the execution of SWM tasks. However, little is known about the temporal structure of mPFC involvement during these tasks, that is during which phase (encoding, maintenance, and/or retrieval) it is actually engaged. In the current study we addressed this issue by recording from and optogenetically silencing mPFC pyramidal neurons in a temporally specific manner while mice performed a non-match-to-sample T-maze task. This task decomposed SWM in three phases (sample, delay and choice phase) that were assumed to capture all memory stages that have to be passed for successful task performance (encoding, maintenance, and retrieval). Once animals had learned the task, testing sessions began in which the mPFC was illuminated with yellow light on half of the trials. In each testing session light delivery was temporally restricted to one of the three phases of the task in order to examine the contribution of the mPFC to different task components. In mice expressing the neural silencer ArchT, light application significantly inhibited the majority of putative pyramidal cells. Furthermore, mPFC inhibition in any of the three phases of the task impaired SWM performance while the same treatment in eGFP control animals had no significant effect on behavior. The results of this experiment suggest that pyramidal neurons in the mPFC are involved in the encoding, maintenance, and retrieval of spatial information. Motivated by recent findings of increased interactions between the mPFC and the ventral tegmental area (VTA) during SWM, a follow-up experiment was conducted, in which we examined whether mPFC projections to the VTA contribute to different aspects of SWM. In order to accomplish projection-specific inhibition of VTA-projecting mPFC neurons, the feasibility of two different optogenetic approaches was tested in head-restrained mice. Based on the results, a terminal inhibition strategy was chosen for reducing prefrontal inputs to the VTA during SWM. By again restricting optogenetic inhibition to different task phases, we found impaired task performance when disrupting mPFC inputs to the VTA during the delay phase, suggesting that this pathway is critical for maintaining, but not encoding or retrieving spatial information.

Keywords: mPFC, spatial working memory, optogenetics
B 01-8

Influence of chemogenetic G-protein coupled receptor modulation of medial prefrontal cortex subregions on attention and waiting impulsivity (#207)

B. van der Veen1, P. Steele-Perkins1, K. Kilonzo1, S. Schulz1, M. Jendryka1, B. Liss1, A. Pekcec2, W. Nissen2, D. Kätzel1

1 University of Ulm, Institute of Applied Physiology, Ulm, Baden-Württemberg, Germany
2 Boehringer Ingelheim Pharma GmbH, Discovery Research, Biberach an der Riss, Germany

Introduction:

A lack of proper attention and impulse control, have been found in many psychiatric disorders, such as ADHD, substance abuse and bipolar disorder. The medial prefrontal cortex (mPFC), has been implicated in attentional control and various forms of impulsivity, e.g. waiting impulsivity, stopping impulsivity, delayed and probabilistic discounting. Lesion studies in rats have implicated the anterior cingulate cortex (ACC) and infralimbic cortex (IL) in impulse control, and the ACC and the prelimbic cortex (PrL) in sustained attention, however the extend of lesions and adaptation effects evoked by them are difficult to delineate. Therefore, we sought to clarify the specific role of the distinct subregions of the PFC in attention and waiting impulsivity in intact animals.

Methods:

We used a chemogenetic approach to selectively activate or inhibit G-protein-cascades on excitatory cells by Designer-Receptors-Exclusively-Activated-by-Designer-Drugs (DREADDs), specifically expressed inexcitatory cells in distinct mPFC subregions of mice. The mice were trained and tested on the five choice serial reaction time task (5CSRTT). Sustained attention and impulse control were assessed on this task by presenting challenges, such as decreased stimulus duration or an increased intertrial interval, respectively. During those challenges, DREADDs are activated by application of different doses of CNO in a latin-square design, counterbalancing for targeted subregion and DREADD/control vector. We also used arterial spin labelling (ASL) to assess the CNO/DREADD-induced activity changes in vivo.

Results:

Using ASL imaging before and after application of CNO (2 mg/kg) we found increased blood flow in the transfected PFC subregion when activating Gq signalling, but not in an untransfected region, proving the capability of DREADDs to activate excitatory cells in vivo. In the 5CSRTT, we found that activating Gi signalling in the ACC by application of CNO decreases premature responding when impulse control is challenged but activation of Gi signalling in the IL does not show such an effect. Activating Gq signalling in the ACC increased premature responding and decreased sustained attention.

Conclusion:

Decreasing activity of excitatory neurons in the ACC but not IL can improve impulse control when challenged.

Keywords: GPCR Signalling, Impulsivity, Attention
B 01-9

Delayed matching to position working memory in mice relies on N-methyl D-aspartate receptors in prefrontal pyramidal cells (#244)

K. Kilonzo1, B. van der Veen1, J. Teutsch1, S. Schulz1, D. Kätzel1

1 Ulm University, Applied Physiology, Ulm, Baden-Württemberg, Germany

Cognitive dysfunction remains an unmet medical need in the treatment of psychiatric and neurological illnesses. These dysfunctions include impairments in attention, cognitive flexibility and memory (working and long-term) and are associated with pathological molecular signalling in the medial prefrontal cortex (mPFC). Working memory is the ability to selectively encode, actively maintain specific information in the mind, and later use it to achieve behavioural goals. Our study focuses on the role of N-methyl D-aspartate receptors (NMDARs) in working memory deficits. Using a mouse model of selective ablation of NMDARs in glutamatergic pyramidal neurons of the mPFC, we examined different components of visuo-spatial working memory with a newly established operant, delayed matching to position (DMTP), task. Targeted knock-down of GluN1 (NMDAR) expression in excitatory cells of the mPFC in adult mice elicited an impairment in DMTP working memory. Surprisingly, the impairment was not observed in the standard, delayed non-matching to position (DNMTP), T-maze rewarded alternation task, suggesting that the cognitive correlates assessed by the two tasks are dissociable. Furthermore, there were no impairments attributable to the knock-down in tests of attention, impulsivity, novelty-induced locomotor hyperactivity, anhedonia, nesting, sociability and anxiety. These results elucidate the multifaceted nature of working memory assessment and suggest that NMDAR-hypofunction in prefrontal excitatory cells may underlie working memory deficits in psychiatric disorders.

Keywords: NMDA receptor, prefrontal pyramidal cells, working memory
B 01-10

Dopamine Neurons Drive Fear Extinction Learning by Signaling the Omission of Expected Aversive Outcomes (#288)

X. I. Salinas-Hernández1, P. Vogel1, R. Kalisch2, T. Sigurdsson1, S. Duvarci1

1 Goethe University Frankfurt, Institute of Neurophysiology, Frankfurt am Main, Hesse, Germany
2 University Medical Center of the Johannes Gutenberg University, Deutsches Resilienz Zentrum, Mainz, Germany

Extinction of fear responses is critical for adaptive behavior and deficits in this form of learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate fear extinction learning are largely unknown. Associative learning theories propose new learning is initiated when outcomes violate our expectations. Such violations are thought to cause “prediction error signals” (PE) that will initiate the neural processes that ultimately lead to behavioral changes. During fear extinction, the absence of an aversive unconditioned stimulus (US) is an unexpected event and likely generates a PE signal that initiates extinction learning. More specifically, the omission of the aversive US can be conceptualized as a better-than-expected outcome. It is well-established that the activity of midbrain dopamine (DA) neurons represents the degree to which outcomes are better or worse than expected. We therefore hypothesized that DA neurons could drive fear extinction learning by signaling the omission of an expected aversive outcome. To address this, we recorded the single-unit spiking activity of ventral tegmental area DA neurons in mice that were trained in a fear conditioning protocol. Analysis of neuronal firing rates during the US omission revealed that a subpopulation of putative DA neurons were significantly excited by the omission of the US during extinction.This DA signal occurred specifically at the beginning of extinction when the US omission is fully unexpected, and correlated strongly with extinction learning. To further confirm that DA neurons signal the unexpected omision of the US, we measured the activity-depended calcium signals selectively in DA neurons using fiber photometry. Consistent with the previous results, we observed a significant increase in the calcium signal at the time of the US omission. Next, we asked whether this signal is necessary for fear extinction. To this end, we performed temporally-specific optogenetic inhibition of DA neurons at the time of the US omission and found that such a manipulation impaired fear extinction learning. Conversely, optogenetic excitation of DA neurons during the US omission accelerated extinction. Together, these results identify a prediction error-like neuronal signal that is necessary to initiate fear extinction and reveal a crucial role of DA neurons in this form of learning. Currently we are investigating which neural circuitry receives the DA-PE signal to drive extinction learning.

Keywords: Fear Extinction Learning, Dopamine
B 01-11

Regulation of locomotion and reward seeking behaviour by the ventral tegmental area inputs onto the lateral hypothalamus (#238)

V. Mykytiuk1, 2, T. Korotkova1, 2

1 Max Planck Institute for Metabolism Research, Neuronal Circuits and Behavior Group, Cologne, North Rhine-Westphalia, Germany
2 University of Cologne, Insitute of Vegetative Physiology, Medical Faculty, Cologne, North Rhine-Westphalia, Germany

To ensure the survival and reproduction animals must adapt their behaviour to acquire rewards and avoid punishments. Rewarding stimuli induce pleasurable feelings and promote approach and consummatory behaviours, eventually leading to behavioural reinforcement. The ventral tegmental area (VTA) and the lateral hypothalamus (LH) are densely interconnected structures, which are critical for reward-seeking behaviour. While the LH-VTA pathway has been recently reported to modulate the approach towards diverse rewarding stimuli, the role of a feedback connection has not yet been investigated.

Here we investigated the role of dopaminergic and GABAergic projections from the ventral tegmental area onto the lateral hypothalamus in reward seeking behaviour of mice. In order to examine how the activity of the LH-projecting dopaminergic and GABAergic VTA cells affects behaviour we optogenetically manipulated these pathways in several behavioural assays.

We found that optogenetic stimulation of VTA-LH dopaminergic projections facilitates locomotion during spontaneous exploration, increasing the average running speed and total distance travelled. It also has an inhibitory effect on feeding in food-deprived mice. Moreover, activation of these projections promotes real-time place preference, which indicates their role in reward processing. Optogenetic stimulation of GABAergic VTA-LH projections, on the contrary,  decreases the locomotory activity of mice and induces food consumption in ad libitum fed mice. In conclusion, optogenetic stimulation of two complementary VTA-LH pathways exhibits opposite effects on reward-seeking behaviour and locomotion in mice, possibly by targeting distinct populations of cells within the LH.

We gratefully acknowledge funding by the ERC Consolidator Grant 2017 (HypFeedNet, TK) and the DFG (233886668/ GRK1960, VM).

Keywords: VTA, LH, Reward
B 01-12

Assessment of executive function after DREADD-mediated inhibition of PV cells in mPFC subregions (#321)

M. Jendryka1, 2, B. van der Veen1, B. Liss1, D. Kätzel1, W. Nissen2, A. Pekcec3

1 University of Ulm, Institute of Applied Physiology, Ulm, Baden-Württemberg, Germany
2 Boehringer Ingelheim, CNS Discovery , Biberach an der Riss, Baden-Württemberg, Germany
3 Boehringer Ingelheim, Research Beyond Borders, Biberach an der Riss, Baden-Württemberg, Germany

This project has been funded by the Boehringer Ingelheim - Ulm University (BIU) Center (TP N10)

Impulse control and attention are key domains in executive function and are impaired in major psychiatric disorders such as schizophrenia, attention- deficit hyperactivity disorder (ADHD) and addiction. Lesion and pharmacological studies have linked distinct subregions of the medial prefrontal cortex with impulsivity and attention, namely the infralimbic cortex (IL) and the anterior cingulate cortex (ACC), respectively.

At the cellular level, parvalbumin (PV) neurons in the mPFC play an important role in the cortical neural network underlying executive function processes. Yet, their functional contribution in distinct mPFC subregions towards impulsive and attentive behavior remains to be elucidated.

Employing DREADD-based chemogenetics, we investigated how the inhibition of PV neurons in the IL or the ACC affected impulsivity and attention assessed in the 5-choice-serial-reaction-time task (5-CSRTT). Though task challenges were able to selectively elicit impulsive (increase in premature responses) or inattentive behavior (decrease of accuracy, increase of omitted responses), differences between hM4Di-injected animals and controls in these domains of executive function were not consistent. In this regard, mice injected with hM4Di in the IL made less incorrect responses during the impulsivity challenge after administering 0.3 mg/kg clozapine (mean diff.: 6.7, n= 7). This was accompanied by a significant increase in the incorrect response latency (time from stimulus presentation until the incorrect response) (mean diff.: 8.8 sec, n= 7). Neither were those effects observed at the same task conditions after administering 10 mg/kg CNO nor in other task challenges.

The results suggest that subregion-specific neural disinhibition in the IL or ACC mediated by inactivating PV neurons may not be sufficient for the consistent modulation of impulsivity or attention. Current endeavors are directed towards investigating the effect of activating PV neurons in these regions as well as focusing on other interneuron types such as somatostatin neurons. 

Keywords: chemogenetics, prefrontal interneurons, 5-CSRTT