Biology subjects

Gunaydin, L. A.

Publications and source records attributed to Gunaydin, L. A..

5 recordsLinked to original sources

bioRxiv2023

Ventromedial Prefrontal Cortex and Basolateral Amygdala Projections to Ventromedial Striatum Encode Active Avoidance Behavior

Active avoidance is a fundamental defensive behavior, defined as performing a voluntary action to escape a noxious stimulus. Active avoidance serves as an adaptive response to threat, ensuring safety. In individuals with anxiety disorders and post-traumatic stress disorder, avoidance behavior can become maladaptive when even safe situations are avoided, at great psychosocial cost. Corticostriatal and amygdalostriatal pathways have been implicated in active avoidance, though their role in learning and expression of this behavior is not fully understood. Projections from the ventromedial prefrontal cortex (vmPFC) to the ventromedial striatum (VMS) have been shown to regulate a variety of defensive behaviors; however, their role in active avoidance has not previously been examined. Additionally, basolateral amygdala (BLA) projections to the VMS have been shown to promote active avoidance in studies utilizing pharmacological inactivation and optogenetic inhibition, though in vivo real time neural activity in this pathway has not been recorded during active avoidance learning. Here we utilized fiber photometry for in vivo recordings of neural activity in vmPFC-VMS and BLA-VMS projections during active avoidance learning and expression. We implemented a two-way signaled active avoidance paradigm in which a light cue served as the conditioned stimulus (CS) signaling an impending foot shock. We examined changes in neural activity in these two projections during CS presentation, onset of active avoidance, and conditioned freezing. We found that vmPFC-VMS projections develop learning-related increases in activity at CS onset across training, while BLA-VMS projections do not show learning-related encoding of the CS. Additionally, we found that both vmPFC-VMS and BLA-VMS projections develop an increase in activity at avoidance onset. No changes in neural activity were observed during cued freezing in either vmPFC-VMS or BLA-VMS projections. Together these results indicate that vmPFC-VMS projections encode both CS and avoidance, while BLA-VMS projections may simply encode avoidance. Finally, we utilized optogenetic inhibition of vmPFC-VMS projections during the CS to investigate the necessity of this pathway for expression of active avoidance behavior. We found that inhibition of vmPFC-VMS projections attenuates learned active avoidance behavior, indicating that activity in this pathway is required for proper active avoidance. In summary, our results demonstrate task-relevant encoding of active avoidance behavior in vmPFC-VMS and BLA-VMS projections.

neuroscience↗

bioRxiv2021

Divergent encoding of active avoidance behavior in corticostriatal and corticolimbic projections

Active avoidance behavior, in which an animal performs an action to avoid a stressor, is crucial for survival and may provide insight into avoidance behaviors seen in anxiety disorders. Active avoidance requires the dorsomedial prefrontal cortex (dmPFC), which is thought to regulate avoidance via downstream projections to the striatum and amygdala. However, the endogenous activity of projection-defined dmPFC subpopulations during active avoidance learning remains unexplored. Here we utilized fiber photometry to record from the dmPFC and its downstream projections to the dorsomedial striatum (DMS) and the basolateral amygdala (BLA) during active avoidance learning in mice. We examined neural activity during conditioned stimulus (CS) presentations, active avoidance, and cued freezing. Both prefrontal projections showed learning-related increases in activity during CS onset throughout active avoidance training. The dmPFC as a whole showed increased activity during avoidance and decreased activity during cued freezing. Finally, dmPFC-DMS and dmPFC-BLA projections showed divergent encoding of active avoidance behavior, with the dmPFC-DMS projection showing increased activity and the dmPFC-BLA showing decreased activity during active avoidance. Our results identify differential prefrontal encoding of active and passive coping behaviors in the same behavioral paradigm and demonstrate divergent encoding of active avoidance in projection-specific dmPFC subpopulations.

neuroscience↗

bioRxiv2021

Parallel valence processing alterations associated with compulsive behavior in SAPAP3 knockout mice and human OCD

Abnormalities in valence processing - the processing of aversive or appetitive stimuli - may be an underrecognized component of obsessive-compulsive disorder (OCD). Independent experimental paradigms have suggested disturbance of emotional valence systems in OCD, yet no standardized assay has been employed to assess both negative and positive valence processing in clinical studies of OCD patients, either at baseline or in response to therapeutic interventions. Additionally, preclinical rodent models are critical for treatment discovery in OCD, yet investigations examining whether rodent models of compulsive behavior similarly show alterations in valence systems have been limited. We sought to establish paradigms for assessing valence processing across both human OCD patients and in a preclinical rodent model: in OCD patients, we used validated behavioral tests to assess explicit and implicit processing of fear-related facial expressions (negative valence) and socially-rewarding happy expressions (positive valence); in the SAPAP3 knockout (KO) mouse model of compulsive behavior, we used auditory fear conditioning and extinction (negative valence) and reward-based operant conditioning (positive valence). We find that OCD patients show enhanced negative and impaired positive valence processing, and that performance on valence processing tasks correlates with clinical measures of OCD severity. We further find that SAPAP3 KO mice show heightened negative and impaired positive valence processing alterations similar to those of OCD patients. Our results show parallel valence processing abnormalities in OCD patients and a preclinical rodent model of compulsive behavior, and suggest valence processing alterations as novel therapeutic targets across a translational research spectrum.

neuroscience↗

bioRxiv2020

Ketamine increases activity of a fronto-striatal projection that regulates compulsive behavior

Obsessive-Compulsive Disorder (OCD), characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions), is associated with dysfunction in fronto-striatal circuits. There are currently no fastacting pharmacological treatments for OCD. However, recent clinical studies demonstrated that an intravenous infusion of ketamine rapidly reduces OCD symptoms. To probe mechanisms underlying ketamines therapeutic effect on OCD-like behaviors, we used the SAPAP3 knockout (KO) mouse model of compulsive grooming. Here we recapitulate the fast-acting therapeutic effect of ketamine on compulsive behavior, and show that ketamine increases activity of dorsomedial prefrontal neurons projecting to the dorsomedial striatum in KO mice. Optogenetically mimicking this increase in fronto-striatal activity rescued compulsive grooming behavior in KO mice. Conversely, inhibiting this circuit in wild-type mice increased grooming. These studies demonstrate that ketamine increases activity in a fronto-striatal circuit that causally controls compulsive grooming behavior, suggesting this circuit may be important for ketamines therapeutic effects in OCD.

neuroscience↗

bioRxiv2020

Fronto-striatal projections regulate approach-avoidance conflict

The dorsomedial prefrontal cortex (dmPFC) has been linked to approach-avoidance behavior and decision-making under conflict, key neural computations thought to be altered in anxiety disorders. However, the heterogeneity of efferent prefrontal projections has obscured identification of the specific top-down neural pathways regulating these anxiety-related behaviors. While the dmPFC-amygdala circuit has long been implicated in controlling reflexive fear responses, recent work suggests that this circuit is less important for avoidance behavior. We hypothesized that dmPFC neurons projecting to the dorsomedial striatum (DMS) represent a subset of prefrontal neurons that robustly encode and drive approach-avoidance behavior. Using fiber photometry recording during the elevated zero maze (EZM) task, we show heightened neural activity in prefrontal and fronto-striatal projection neurons, but not fronto-amydalar projection neurons, during exploration of the anxiogenic open arms of the maze. Additionally, through pathway-specific optogenetics we demonstrate that this fronto-striatal projection preferentially excites postsynaptic D1 receptor-expressing medium spiny neurons in the DMS and bidirectionally controls avoidance behavior. We conclude that this striatal-projecting subpopulation of prefrontal neurons regulates approach-avoidance conflict, supporting a model for prefrontal control of defensive behavior in which the dmPFC-amygdala projection controls reflexive fear behavior and the dmPFC-striatum projection controls anxious avoidance behavior. Our findings identify this fronto-striatal circuit as a valuable therapeutic target for developing interventions to alleviate excessive avoidance behavior in anxiety disorders.

neuroscience↗