Biology subjects

Mermelstein, P. G.

Publications and source records attributed to Mermelstein, P. G..

7 recordsLinked to original sources

bioRxiv2025

Cocaine sensitization and accumbens shell plasticity depend on biological sex and gonadal hormones in C57BL/6J mice

Biological sex as a defining variable in drug sensitivity remains poorly understood. Here, we combine behavioral and electrophysiological analyses to examine the influence of sex and gonadal hormones on cocaine-induced psychomotor sensitization and nucleus accumbens shell (NAcSh) plasticity in the prominent C57BL/6J mouse strain. Males exhibited greater cocaine-evoked locomotor activity than females; castration attenuated responses, whereas ovariectomy enhanced them. This behavioral phenotype is opposite to what occurs in rats. A 10-14 day abstinence period abolished the sex difference in intact animals, and gonadectomy reduced cocaine-induced behavioral plasticity. Recordings from 309 medium spiny neurons revealed sex-dependent NAcSh plasticity. In males, cocaine decreased neuronal excitability, while in females it induced estrous cycle-dependent plasticity characterized by reduced excitability during diestrus relative to estrus. These effects were driven by cocaine-induced modulation of voltage-gated sodium channels. Cocaine potentiated glutamatergic strength in males but elicited estrous cycle-dependent depotentiation in females. These adaptations in excitability and glutamatergic strength were abolished by gonadectomy, and paralleled diminished behavioral plasticity during abstinence. These data illustrate that biological sex and hormonal milieu critically shape cocaine-induced plasticity, offering a more nuanced framework than the traditional notion of heightened female sensitivity to drugs of abuse.

neuroscience↗

bioRxiv2025

Fundamental Sex Differences in Cocaine-Induced Plasticity of D1R- and D2R-MSNs in the Mouse Nucleus Accumbens Core

BACKGROUNDPrevious studies have shown that cocaine-induced changes in nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs) differ based on dopamine receptor subtype expression, the sex of the animal, and for females, phase of the estrous cycle. These findings highlight the need to account for both sex and estrous cycle when studying drug-mediated alterations in neurophysiology. Whether MSNs of the nucleus accumbens core (NAcC), which serve different aspects of addiction, will exhibit similar sex and estrous cycle effects with cocaine administration was investigated. METHODSMice underwent a 5-day locomotor sensitization paradigm via daily cocaine administration (15 mg/kg, s.c.) followed by a 1-to 4-day drug-free abstinence period. We examined NAcC MSN excitability by obtaining ex vivo whole-cell recordings from differentially labeled dopamine D1-receptor expressing MSNs (D1R-MSNs) and dopamine D2-receptor expressing MSNs (D2R-MSNs) obtained from male mice or female mice that were either in estrus or diestrus. RESULTSIn this genetic background of mice, both male and female mice sensitized to cocaine in a similar manner. In males, there were no cocaine-induced changes in D1R-MSN or D2R-MSN excitability, with D2R-MSNs exhibiting greater excitability. In saline-treated females, D1R-MSN excitability fluctuated across the estrous cycle with increased excitability during estrus. Following cocaine, estrous cycle-dependent D1R-MSN excitability was arrested, fixed at an intermediate value between estrus and diestrus when compared to saline controls. D2R-MSNs did not change either across the estrous cycle or following cocaine. When comparing MSN subtypes, in diestrus, D2R-MSNs were more excitable under saline conditions, but indistinguishable from D1R-MSNs following cocaine. In contrast, during estrus, D1R-and D2R-MSN excitability was similar in saline treated animals, but with cocaine, D2R-MSNs displayed heightened excitability. CONCLUSIONSThere are fundamental sex differences in cocaine-induced changes to the excitability of D1R-MSNs in the NAcC. After cocaine exposure, female mice in diestrus exhibited a significant main effect change in MSN excitability, an inversion of what had previously been demonstrated in the NAcSh where no cocaine-induced changes were observed. These data suggest that there are distinct differences in the neuropharmacological effect of cocaine in males versus females that are shell and core specific. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/660420v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@fdb01corg.highwire.dtl.DTLVardef@1350b15org.highwire.dtl.DTLVardef@16aac03org.highwire.dtl.DTLVardef@433842_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSThere are sex-and estrous-cycle dependent changes to D1R-MSNs in the NAcC that are sensitive to cocaine exposure. In males, cocaine has no effect on D1R-or D2R-MSNs excitability. During the estrous cycle, D1R-MSNs exhibit increased excitability during estrus. This fluctuation is halted by cocaine, such that D1R-MSNs recorded in diestrus show increased excitability following cocaine exposure whereas female D1R-MSNs recorded in estrus have decreased excitability. PLAIN LANGUAGE SUMMARYThe nucleus accumbens core (NAcC) is a brain region associated with regulating motivated behavior. The primary neuronal populations of the NAcC are dopamine D1 receptor expressing medium spiny neurons (D1R-MSNs) and dopamine D2 receptor expressing medium spiny neurons (D2R-MSNs). No studies exist which examine sex differences and estrous cycle effects in the NAcC following cocaine administration. Using ex vivo electrophysiology, we found inherent sex-and estrous-cycle differences in cocaine-induced changes in MSN neuroplasticity. D1R-MSN excitability was unaffected in males, increased in females recorded during the diestrus phase, and decreased in females recorded during estrus following cocaine exposure. This ran counter to estrous cycle effects under drug-naive conditions where D1R-MSN excitability was higher in estrus versus diestrus. The estrous cycle effects on D1R-MSNs were eliminated following cocaine administration. For both sexes, D2R-MSN excitability was not impacted following cocaine. These results highlight fundamental sex differences that might underpin differences in substance abuse.

neuroscience↗

bioRxiv2024

Cholinergic interneurons in the nucleus accumbens are a site of cellular convergence for corticotropin release factor and estrogen regulation

Cholinergic interneurons (ChIs) act as master regulators of striatal output, finely tuning neurotransmission to control motivated behaviors. ChIs are a cellular target of many peptide and hormonal neuromodulators, including corticotropin releasing factor, opioids, insulin and leptin, which can influence an animals behavior by signaling stress, pleasure, pain and nutritional status. However, little is known about how sex hormones via estrogen receptors influence the function of these other neuromodulators. Here, we performed in situ hybridization on mouse striatal tissue to characterize the effect of sex and sex hormones on choline acetyltransferase (Chat), estrogen receptor alpha (Esr1), and corticotropin releasing factor type 1 receptor (Crhr1) expression. Although we did not detect sex differences in ChAT protein levels in the striatum, we found that female mice have more Chat mRNA-expressing neurons than males. At the population level, we observed a sexually dimorphic distribution of Esr1- and Crhr1-expressing ChIs in the ventral striatum that demonstrates an antagonistic correlational relationship, which is abolished by ovariectomy. Only in the NAc did we find a significant population of ChIs that co-express Crhr1 and Esr1. At the cellular level, Crhr1 and Esr1 transcript levels were negatively correlated only during estrus, indicating that changes in sex hormones levels can modulate the interaction between Crhr1 and Esr1 mRNA levels. Together, these data provide evidence for the unique expression and interaction of Esr1 and Crhr1 in ventral striatal ChIs, warranting further investigation into how these transcriptomic patterns might underlie important functions for ChIs at the intersection of stress and reproductive behaviors.

neuroscience↗

bioRxiv2023

Fundamental Sex Differences in Cocaine-Induced Plasticity of D1- and D2-MSNs in the Mouse Nucleus Accumbens Shell

Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in D1 dopamine receptor expressing neurons (D1-MSNs), with little if any impact on D2 dopamine receptor neurons (D2-MSNs). Using ex vivo whole cell recordings in male and female mice, we observe alterations in D1-MSN excitability across the estrous cycle similar in magnitude to the actions of cocaine in males. Furthermore, cocaine shifts estrous cycle-dependent plasticity from intrinsic excitability changes in D1-MSNs to D2-MSNs. Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1-MSN versus D2-MSN between the sexes, in males this is mediated through reduced D1-MSN excitability, whereas in females it is due to heightened D2-MSN excitability.

neuroscience↗

bioRxiv2023

Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell neurons via NMDAR activation in a sex-dependent manner

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4g/kg) to acetic acid in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males>females). Ex vivo electrophysiology recordings of NAcSh neurons in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh neuronal excitability in both sexes. N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5, and memantine robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain.

neuroscience↗

bioRxiv2022

Neuroligin-3 in Dopamine Neurons Promotes Behavioral and Neurobiological Adaptations to Chronic Morphine Exposure

Chronic opioid exposure causes structural and functional changes in brain circuits, which may contribute to opioid use disorders. Synaptic cell-adhesion molecules are prime candidates for mediating this opioid-evoked plasticity. Neuroligin-3 (NL3) is an X-linked postsynaptic adhesion protein that shapes synaptic function at multiple sites in the mesolimbic dopamine system. We therefore studied how genetic knockout of NL3 alters responses to chronic morphine in male mice. Constitutive NL3 knockout caused a persistent reduction in psychomotor sensitization after chronic morphine exposure and changed in the topography of locomotor stimulation produced by morphine. This latter change was recapitulated by conditional genetic deletion of NL3 from cells expressing the Drd1 dopamine receptor, whereas reduced psychomotor sensitization was recapitulated by conditional genetic deletion from dopamine neurons. Without NL3 expression, dopamine neurons in the ventral tegmental area exhibited diminished activation following chronic morphine exposure, by measuring in vivo calcium signals with fiber photometry. This altered pattern of dopamine neuron activity may be driven by aberrant forms of opioid-evoked synaptic plasticity in the absence of NL3: dopamine neurons lacking NL3 showed weaker synaptic inhibition at baseline, which was subsequently strengthened after chronic morphine. In total, our study highlights neurobiological adaptations in dopamine neurons of the ventral tegmental area that correspond with increased behavioral sensitivity to opioids, and further suggests that NL3 expression by dopamine neurons provides a molecular substrate for opioid-evoked adaptations in brain function and behavior.

neuroscience↗

bioRxiv2020

Effects of gonadectomy and androgen on neuronal plasticity in motivation and reward related brain regions in the male rat

Gonadal hormones affect neuronal morphology to ultimately regulate behavior. Here, we investigated the effect of both castration and androgen replacement on spine plasticity in the nucleus accumbens shell and core (NAcSh and NAcC), caudate putamen (CPu), medial amygdala (MeA), and medial preoptic nucleus (MPN). Intact and castrated (GDX) male rats were treated with dihydrotestosterone (DHT, 1.5mg) or vehicle (oil) in 3 experimental groups: intact-oil, GDX-oil and GDX-DHT. Spine density and morphology, measured 24 hours after injection, were determined through 3D reconstruction of DiI-labeled dendritic segments. GDX decreased spine density in the MPN, which was rescued by DHT treatment. MeA spine density increased in GDX-DHT animals compared to intact-oil animals. In the NAcSh, DHT decreased spine density, and also rapidly increased the number of pCREB+ cell bodies. These findings indicate that androgen signaling plays a role in the regulation of spine plasticity within neurocircuits involved in motivated behaviors.

neuroscience↗