Biology subjects

Kohut, S. J.

Publications and source records attributed to Kohut, S. J..

3 recordsLinked to original sources

bioRxiv2026

Δ⁹-Tetrahydrocannabinol-induced enhancement of reward responsivity via mesocorticolimbic modulation in squirrel monkeys

{Delta}9-tetrahydrocannabinol (THC)-containing products are widely used recreationally, partly due to THCs ability to enhance the appetitive (i.e., rewarding) properties of diverse stimuli. However, the neural mechanisms through which THC modulates reward-related processing remain poorly understood. Here, we used a Pavlovian paradigm in adult squirrel monkeys (3males, 1female) to associate a visual conditioned stimulus (CS+) with appetitive food delivery. The modulatory effects of acute THC (1-10g/kg, i.m.) on behavioral and brain responses to CS+ were evaluated. Event-related functional MRI (fMRI) was employed to characterize the neural correlates of conditioned responding to the CS+, both in the absence and presence of THC treatment, with preconditioning scans serving as control. Behaviorally, THC (3g/kg) selectively enhanced conditioned responding to the CS+ without altering responses to the control stimulus (CS-) or increasing baseline consummatory responding, underscoring the specificity of THCs action on reward-associated processes. Consistently, fMRI analyses revealed that THC amplified CS+-evoked activation within mesocorticolimbic regions, including the anterior cingulate cortex (ACC), striatum, hippocampus, and substantia nigra-ventral tegmental area (SN-VTA), without affecting activity in visual and motor cortices. This finding underscores the selectivity of THCs neuromodulatory effects on reward-related circuitry. Independent of CS exposure, resting-state functional connectivity analyses indicate that THC enhanced mesocorticolimbic network integration, as evident in strengthened SN-VTA-centered connectivity with the ACC, striatum, and hippocampus. Collectively, these findings demonstrate that THC enhances the responses to appetitive stimuli, through selective modulation of mesocorticolimbic circuitry, highlighting the SN-VTA as a pivotal hub for cannabinoid-mediated regulation of incentive salience and motivational drive toward reward-associated stimuli. One-sentence summariesTHC enhances behavioral and neural responses to rewards through mesocorticolimbic modulation centered on the SN-VTA.

neuroscience↗

bioRxiv2025

Nociceptin/Orphanin FQ receptor agonism attenuates behavioral and neural responses to conditioned aversive stimuli

The nociceptin/orphanin FQ peptide (NOP) receptor has emerged as a promising anxiolytic target, as its activation has been shown to reduce anxiety-related behaviors in rodents. However, the mechanisms underlying these effects are not well understood. Here, we investigated the effects of the selective NOP receptor agonist SCH-221510 (SCH; 0.01-0.1 mg/kg, IM) on behavioral and neural responses to aversive stimuli in squirrel monkeys (n=3). Subjects underwent Pavlovian fear conditioning, wherein a visual conditioned stimulus (CS) was paired with the presentation of an aversive stimulus. Event-related fMRI was conducted in awake subjects to evaluate CS-evoked neural responses. Behavioral and neural responses to the CS were assessed across three experimental phases: pre-conditioning (Pre-C), post-conditioning (Post-C), and Post-C with SCH administration. In behavioral assessments, CS presentation during Post-C elicited a robust suppression of ongoing operant responding, which was absent during Pre-C and significantly attenuated by SCH treatment (0.1 mg/kg). Functional magnetic resonance imaging (fMRI) results revealed that, relative to Pre-C, CS presentation during Post-C was associated with increased BOLD activity in brain regions previously implicated in fear processing (e.g., amygdala), expression and regulation (e.g., prefrontal cortex; PFC), as well as sensory integration. Critically, SCH (0.1 mg/kg) administration significantly attenuated CS-induced neural activation in these regions. Furthermore, resting-state functional connectivity analysis revealed that SCH administration decreased connectivity between the PFC and the amygdala, while enhancing connectivity among subregions of the PFC. Collectively, these findings suggest that NOP receptor agonism may attenuate conditioned responses to aversive stimuli by modulating functional interactions within the PFC-amygdala circuit.

neuroscience↗

bioRxiv2023

Single nucleus transcriptomics of human and monkey striatum implicates DNA damage, neuroinflammation, and neurodegeneration signaling in opioid use disorder

The striatum in the brain is involved in various behavioral functions, including reward, and disease processes, such as opioid use disorder (OUD). Further understanding of the role of striatal subregions in reward behaviors and their potential associations with OUD requires molecular identification of specific striatal cell types in human brain. The human striatum contains subregions based on different anatomical, functional, and physiological properties, with the dorsal striatum further divided into caudate and putamen. Both caudate and putamen are involved in altered reward processing, formation of habits, and development of negative affect states associated with OUD. Using single nuclei RNA-sequencing of human postmortem caudate and putamen, we identified canonical neuronal cell types in striatum (e.g., dopamine receptor 1 or 2 expressing neurons, D1 or D2) and less abundant subpopulations, including D1/D2-hybrid neurons and multiple classes of interneurons. By comparing unaffected subjects to subjects with OUD, we found neuronal-specific differences in pathways related to neurodegeneration, interferon response, and DNA damage. DNA damage markers were also elevated in striatal neurons of rhesus macaques following chronic opioid administration. We also identified sex-dependent differences in the expression of stress-induced transcripts among astrocytes and oligodendrocytes from female subjects with OUD. Thus, we describe striatal cell types and leverage these data to gain insights into molecular alterations in human striatum associated with opioid addiction.

neuroscience↗