Biology subjects

McReynolds, J. R.

Publications and source records attributed to McReynolds, J. R..

4 recordsLinked to original sources

bioRxiv2026

Projections from subfornical organ to infralimbic cortex modulate carbon dioxide associated fear

Most of our mechanistic understanding of threat responding and defensive fear behaviors is based on exposure to aversive stimuli in the environment. However, unpleasant, within-the body interoceptive signals can also regulate threat and emotion although underlying cell-circuit mechanisms are not well understood. Abnormal interoceptive sensitivity is associated with fear-associated psychiatric conditions such as panic disorder and PTSD. The ventromedial infralimbic (IL) subdivision of the prefrontal cortex plays a key role in threat appraisal and fear, however, IL engagement in interoceptive threat response and contributory afferent mechanisms are not known. Here, using an interoceptive clinical panicogen, carbon dioxide (CO2) inhalation, we report IL-mediated regulation of fear in mice via afferents from the subfornical organ (SFO), a key viscero-humoral circumventricular organ lacking a traditional blood brain barrier. Chemogenetic inhibition of SFO-to-IL (but not SFO-to-BNST) projections regulated defensive behaviors during CO2 inhalation and associative contextual fear. Notably, the SFO-IL circuit also modulated delayed CO2 effects on contextual fear conditioning-extinction, but not startle, neuroendocrine response or motivated behaviors. We also established more specifically that SFO angiotensin II receptor type-1 (AT-1R)+ve neuronal afferents to the IL regulate CO2-associated fear and long-term deficits in contextual fear extinction. CO2 inhalation reduced neuronal activation within the IL and optogenetic activation of SFO neurons activated inhibitory parvalbumin (PV) (but not somatostatin (SST)) interneurons in the IL. Collectively, these data reveal that aversive interoceptive signals can be directly conveyed to the IL via the SFO, a sensory hub for systemic perturbations, to regulate spontaneous and long-term fear. Our findings provide important mechanistic insights into fear-associated disorders with abnormal interoceptive threat sensitivity such as panic disorder and PTSD.

neuroscience↗

bioRxiv2026

Sex-specific differences in endocannabinoid regulation of cocaine-evoked dopamine in the medial nucleus accumbens shell

Endocannabinoid (eCB) signaling is a key regulator of reward-related dopaminergic signaling, particularly in response to drugs of abuse, such as cocaine. To date, our understanding of this mechanism has primarily been limited to male subjects. Prior work establishes that female cocaine users have more adverse outcomes, and female rats show greater sensitivity to cannabinoid type 1 receptor (CB1R) regulation of cocaine self-administration. Therefore, we hypothesize that female rats exhibit enhanced eCB regulation of cocaine-evoked dopamine (DA). We used in vivo fiber photometry recording of the dopamine biosensor, dLight 1.3b, in the nucleus accumbens medial shell (NAcms) in response to cocaine in male and female rats. Rats were pretreated with cannabinoid-targeting drugs to investigate the effects of CB1R inactivation or augmentation of the eCB 2-AG on cocaine-evoked DA. Our results revealed that CB1R inactivation attenuates cocaine-evoked DA in male and female rats, but females showed enhanced sensitivity for CB1R regulation of cocaine-evoked DA. Cocaine-evoked DA was enhanced by augmenting 2-AG levels, and females again showed increased sensitivity to this manipulation. Finally, females show greater cocaine-evoked DA when in a non-estrous cycle compared to estrous, reinforcing that estrous cycle is a determinant of cocaine-evoked DA. These data indicate that females show enhanced eCB regulation of cocaine-evoked DA signaling, underscoring the importance of sex as a biological variable in our understanding of endocannabinoid regulation of drug reward. HighlightsO_LICB1R inactivation attenuates cocaine-evoked DA in NAcms, preferentially in females C_LIO_LI2-AG augmentation via MAGL inhibition enhances cocaine-evoked DA, with female bias C_LIO_LIEstrous phase modulates the dopamine response to a high dose of cocaine in females C_LIO_LIMale and female rats show similar baseline DA and locomotor responses to cocaine C_LI

neuroscience↗

bioRxiv2023

Repeated footshock stress induces an escalation of cocaine self-administration in male and female rats: Role of the cannabinoid receptor 1

Stress is a significant contributor to the development and progression of substance use disorders (SUDs) and is problematic as it is unavoidable in daily life. Therefore, it is important to understand the neurobiological mechanisms that underlie the influence of stress on drug use. We have previously developed a model to examine the contribution of stress to drug-related behavior by administering a stressor, electric footshock stress, daily at the time of cocaine self-administration in rats resulting in an escalation of cocaine intake. This stress-induced escalation of cocaine intake involves neurobiological mediators of stress and reward such as cannabinoid signaling. However, all of this work has been conducted in male rats. Here we test the hypothesis that repeated daily stress can produce an escalation of cocaine in both male and female rats. We further hypothesize that cannabinoid receptor 1 (CB1R) signaling is recruited by repeated stress to influence cocaine intake in both male and female rats. Male and female Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during a modified short-access paradigm wherein the 2-hr access was separated into 4-30 min self-administration blocks separated by 4-5 min drug free period. Footshock stress produced a significant escalation of cocaine intake similarly in both male and female rats. Female stress-escalated rats did display greater time-out non-reinforced responding and greater "front-loading" behavior. In males, systemic administration of a CB1R inverse agonist/antagonist Rimonabant only attenuated cocaine intake in rats with a history of combined repeated stress and cocaine self-administration. However, in females, Rimonabant attenuated cocaine intake in the no stress control group but only at the highest dose of Rimonabant (3 mg/kg, i.p.) suggesting that females show a greater sensitivity to CB1R antagonism. However, female rats with a history of stress showed even greater sensitivity to CB1R antagonism as both doses of Rimonabant (1, 3 mg/kg) attenuated cocaine intake in stress-escalated rats similar to males. Altogether these data demonstrate that stress can produce significant changes in cocaine self-administration and suggests that repeated stress at the time of cocaine self-administration recruits CB1Rs to regulate cocaine-taking behavior across sexes.

neuroscience↗

bioRxiv2022

Role of mesolimbic endocannabinoid signaling in stress-driven cocaine use in rats

Stress is prevalent in the lives of those with substance use disorders (SUDs) and influences SUD outcomes. Understanding the neurobiological mechanisms through which stress promotes drug use is important for the development of effective SUD interventions. We have developed a model wherein exposure to a stressor, uncontrollable electric footshock, daily at the time of cocaine self-administration (SA) escalates intake in male rats. Here we test the hypothesis that stress-induced escalation of cocaine SA requires CB1 cannabinoid receptor signaling. Male Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during 2-h sessions comprised of four 30-min SA components separated by 5-min shock sequences or 5-min shock-free periods for 14 days. Footshock produced an escalation of cocaine SA that persisted following shock removal. Systemic administration of the cannabinoid receptor type 1 (CB1R) antagonist, AM251, attenuated cocaine intake only in rats with a history of stress. This effect was localized to the mesolimbic system, as intra-nucleus accumbens (NAc) shell and intra-ventral tegmental area (VTA) micro-infusions of AM251 attenuated cocaine intake only in stress-escalated rats. Cocaine SA, regardless of stress history, increases CB1R binding site density in the VTA, but not NAc shell. Following extinction, cocaine-primed reinstatement (10 mg/kg, ip) was increased in rats with prior footshock during SA. AM251 attenuated reinstatement only in rats with a stress history. Altogether, these data demonstrate that mesolimbic CB1R signaling is required to escalate intake and heighten relapse susceptibility and suggest that repeated stress at the time of cocaine use enhances mesolimbic CB1R signaling through a currently unknown mechanism.

neuroscience↗