Biology subjects

Spencer, C. D.

Publications and source records attributed to Spencer, C. D..

3 recordsLinked to original sources

bioRxiv2025

Fos expression in the periaqueductal gray, but not the ventromedial hypothalamus, is correlated with psychosocial stress-induced cocaine-seeking behavior in rats

Psychosocial stressors are known to promote cocaine craving and relapse in humans but are infrequently employed in preclinical relapse models. Consequently, the underlying neural circuitry by which these stressors drive cocaine seeking has not been thoroughly explored. Using Fos expression analyses, we sought to examine whether the ventromedial hypothalamus (VMH) or periaqueductal gray (PAG), two critical components of the brains hypothalamic defense system, are activated during psychosocial stress-induced cocaine seeking. Adult male and female rats self-administered cocaine (0.5 mg/kg/inf IV, fixed-ratio 1 schedule, 2 h/session) over 20 sessions. On sessions 11, 14, 17, and 20, a tactile cue was present in the operant chamber that signaled impending social defeat stress (n=16, 8/sex), footshock stress (n=12, 6/sex), or a no-stress control condition (n=12, 6/sex) immediately after the sessions conclusion. Responding was subsequently extinguished, and rats were tested for reinstatement of cocaine seeking during re-exposure to the tactile cue that signaled their impending stress/no-stress post-session event. All experimental groups displayed significant reinstatement of cocaine seeking, but Fos analyses indicated that neural activity within the rostrolateral PAG (rPAGl) was selectively correlated with cocaine-seeking magnitude in the socially-defeated rats. rPAGl activation was also associated with active-defense coping behaviors during social defeat encounters and with Fos expression in prelimbic prefrontal cortex and orexin-negative cells of the lateral hypothalamus/perifornical area in males, but not females. These findings suggest a potentially novel role for the rPAGl in psychosocial stress-induced cocaine seeking, perhaps in a sex-dependent manner.

neuroscience↗

bioRxiv2023

Inhibitory actions of melanin-concentrating hormone in the lateral septum

Melanin-concentrating hormone (MCH) neurons can coexpress several neuropeptides or neurotransmitters and send widespread projections throughout the brain. Notably, there is a dense cluster of nerve terminals from MCH neurons in the lateral septum (LS) that innervate LS cells by glutamate release. The LS is also a key region integrating stress- and anxiety-like behaviours that are also emerging roles of MCH neurons. However, it is not known if the MCH peptide acts within the LS or whether MCH target sites are localized. We analysed the projections from MCH neurons in male and female mice anteroposteriorly throughout the LS and found spatial overlap between the distribution pattern of MCH-immunoreactive (MCH-ir) fibers with MCH receptor Mchr1 mRNA hybridization or MCHR1-ir cells. This overlap was most prominent along the ventral and lateral border of the rostral part of the LS (LSr). Most MCHR1-labeled LS neurons laid adjacent to passing MCH-ir fibers, but some MCH-ir varicosities directly contacted the soma or cilium of MCHR1-labeled LS neurons. We thus performed whole-cell patch-clamp recordings from MCHR1-rich LSr regions to determine if and how LS cells respond to MCH. Bath application of MCH to acute brain slices activated a bicuculline-sensitive chloride current that directly hyperpolarized LS cells. This MCH-mediated hyperpolarization was blocked by calphostin C and suggested that the inhibitory actions of MCH were mediated by protein kinase C-dependent activation of GABAA receptors. Taken together, these findings defined potential hotspots within the LS that may elucidate the contributions of MCH to stress- or anxiety-related feeding behaviours. Key pointsO_LIRESEARCH QUESTION. Melanin-concentrating hormone (MCH) neurons have dense nerve terminals within the lateral septum (LS), a key region underlying stress- and anxiety-like behaviours that are emerging roles of the MCH system, but it is not known if the LS is a MCH target site. C_LIO_LINEUROANATOMY. We found spatial overlap between MCH-immunoreactive fibers, Mchr1 mRNA, and MCHR1 protein expression especially along the lateral border of the LS. C_LIO_LIELECTROPHYSIOLOGY. Within MCHR1-rich regions, MCH directly inhibited LS cells by increasing a chloride conductance in a protein kinase C-dependent manner. C_LIO_LISIGNIFICANCE. Electrophysiological MCH effects in brain slices have been elusive and even fewer have described the mechanisms of MCH action. Our findings demonstrated, to our knowledge, the first description of MCHR1 Gq-coupling in brain slices, which was previously predicted in cell or primary culture models only. Together, these findings defined hotspots and mechanistic underpinnings for MCH effects such as in stress- and anxiety-related behaviours. C_LI

neuroscience↗

bioRxiv2023

Regulation of the mouse ventral tegmental area by melanin-concentrating hormone

Melanin-concentrating hormone (MCH) acts via its sole receptor MCHR1 in rodents and is an important regulator of homeostatic behaviors like feeding, sleep, and mood to impact overall energy balance. The loss of MCH signaling by MCH or MCHR1 deletion produces hyperactive mice with increased energy expenditure, and these effects are consistently associated with a hyperdopaminergic state. We recently showed that MCH suppresses dopamine release in the nucleus accumbens, which principally receives dopaminergic projections from the ventral tegmental area (VTA), but the mechanisms underlying MCH-regulated dopamine release are not clearly defined. MCHR1 expression is widespread and includes dopaminergic VTA cells. However, as the VTA is a neurochemically diverse structure, we assessed Mchr1 gene expression at glutamatergic, GABAergic, and dopaminergic VTA cells and determined if MCH inhibited the activity of VTA cells and/or their local microcircuit. Mchr1 expression was robust in major VTA cell types, including most dopaminergic (78%) or glutamatergic cells (52%) and some GABAergic cells (38%). Interestingly, MCH directly inhibited dopaminergic and GABAergic cells but did not regulate the activity of glutamatergic cells. Rather, MCH produced a delayed increase in excitatory input to dopamine cells and a corresponding decrease in GABAergic input to glutamatergic VTA cells. Our findings suggested that MCH may acutely suppress dopamine release while disinhibiting local glutamatergic signaling to restore dopamine levels. This indicated that the VTA is a target of MCH action, which may provide bidirectional regulation of energy balance. Significance StatementRole of melanin-concentrating hormone (MCH) on energy balance may converge on the dopamine system via the mesolimbic pathway, as loss of MCH or MCH receptor (MCHR1) signaling increases hyperactivity and energy expenditure associated with a hyperdopaminergic state. MCH can suppress dopamine release within the mesolimbic pathway, but its underlying mechanism is not known. We thus determined if MCH could inhibit dopamine release through direct actions within the ventral tegmental area (VTA). We found that MCH directly inhibited dopaminergic VTA cells, but MCH also disinhibited excitatory input to dopamine cells. Therefore, we showed that the VTA is a putative target site supporting dopamine-dependent actions of MCH.

neuroscience↗