Biology subjects

Ray, M. H.

Publications and source records attributed to Ray, M. H..

5 recordsLinked to original sources

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↗

bioRxiv2021

Distinct threat and valence signals in rat nucleus accumbens core

Appropriate responding to threat and reward is essential to survival. The nucleus accumbens core (NAcc) is known to support and organize reward behavior. More recently our laboratory has shown the NAcc is necessary to discriminate cues for threat and safety. To directly reveal NAcc threat responding, we recorded single-unit activity from 7 female rats undergoing Pavlovian fear discrimination. Rats fully discriminated cues for danger, uncertainty, and safety. Demonstrating direct threat responding, most NAcc neurons showed greatest firing changes to danger and uncertainty. Heterogeneity in cue and reward firing led to the detection of multiple, functional populations. One NAcc population specifically decreased firing to threat (danger and uncertainty). A separate population bi-directionally signaled valence through firing decreases to negative valence events (danger and uncertainty) and opposing firing increases to positive valence events (reward and safety onset). The findings point to the NAcc as a neural source of threat information and a more general valence hub.

neuroscience↗

bioRxiv2020

Foot shock facilitates reward seeking in an experience-dependent manner

Animals organize reward seeking around aversive events. An abundance of research shows that foot shock, as well as a shock-associated cue, can elicit freezing and suppress reward seeking. Yet, there is evidence that experience can flip the effect of foot shock to facilitate reward seeking. Here we examine cue suppression, foot shock suppression and foot shock facilitation of reward seeking in a single behavioural setting. Male Long Evans rats received fear discrimination consisting of danger, uncertainty and safety cues. Discrimination took place over a baseline of rewarded nose poking. With limited experience, all cues and foot shock strongly suppressed reward seeking. With continued experience, suppression became specific to shock-associated cues and foot shock facilitated reward seeking. Our results provide a means of assessing positive properties of foot shock, and may provide insight into maladaptive behavior around aversive events.Competing Interest StatementThe authors have declared no competing interest.View Full Text

animal behavior and cognition↗

bioRxiv2020

Ventral pallidum neurons signal relative threat

Ventral pallidum (VP) neurons scale firing increases to reward value and decrease firing to aversive cues. Anatomical connectivity suggests a critical role for the VP in threat-related behavior. Here we tested whether firing decreases in VP neurons conform to relative threat by recording single units while male rats discriminated cues predicting unique foot shock probabilities. Rats behavior and VP single unit firing discriminated danger, uncertainty and safety cues. We found that two VP populations (Low firing and Intermediate firing) signaled relative threat, proportionally decreased firing according shock probability: danger < uncertainty < safety. Low firing neurons showed reward firing increases, consistent with a general signal for relative value. Intermediate firing neurons were unresponsive to reward, revealing a specific signal for relative threat. The results suggest an integral role for the VP in threat-related behavior.

neuroscience↗

bioRxiv2020

The nucleus accumbens core is necessary to scale fear to degree of threat

Fear is adaptive when the level of the response rapidly scales to degree of threat. Using a discrimination procedure consisting of danger, uncertainty and safety cues, we have found rapid fear scaling (within two seconds of cue presentation) in male rats. Here we examined a possible role for the nucleus accumbens core (NAcc) in the acquisition and expression of fear scaling. In experiment 1, male Long Evans rats received bilateral sham or neurotoxic NAcc lesions, recovered and underwent fear discrimination. NAcc-lesioned rats were generally impaired in scaling fear to degree of threat, and specifically impaired in rapid uncertainty-safety discrimination. In experiment 2, male Long Evans rats received NAcc transduction with halorhodopsin or a control fluorophore. After fear scaling was established, the NAcc was illuminated during cue or control periods. NAcc-halorhodopsin rats receiving cue illumination were specifically impaired in rapid uncertainty-safety discrimination. The results reveal a general role for the NAcc in scaling fear to degree of threat, and a specific role in rapid discrimination of uncertain threat and safety. Significance StatementRapidly discriminating cues for threat and safety is essential for survival and impaired threat-safety discrimination is a hallmark of stress and anxiety disorders. In two experiments, we induced nucleus accumbens core (NAcc) dysfunction in rats receiving fear discrimination consisting of cues for danger, uncertainty and safety. Permanent NAcc dysfunction, via neurotoxic lesion, generally disrupted the ability to scale fear to degree of threat, and specifically impaired one component of scaling: rapid discrimination of uncertain threat and safety. Reversible NAcc dysfunction, via optogenetic inhibition, specifically impaired rapid discrimination of uncertain threat and safety. The results reveal that the NAcc is essential to scale fear to degree of threat, and is a plausible source of dysfunction in stress and anxiety disorders.

neuroscience↗