Sex differences in membrane properties and cellular excitability of dopamine D1 receptor-expressing neurons within the shell of the nucleus accumbens of pre- and mid-adolescent mice.

ABSTRACT

BACKGROUND: The transition from childhood to adulthood, or adolescence, a developmental stage, is characterized by psychosocial and biological changes. The nucleus accumbens (NAc), a striatal brain region composed of the core (NAcC) and shell (NAcSh), has been linked to risk-taking behavior and implicated in reward seeking and evaluation. Most neurons in the NAc are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1R +) and/or dopamine D2 receptors (D2R +). Changes in dopaminergic and glutamatergic systems occur during adolescence and converge in the NAc. While there are previous investigations into sex differences in membrane excitability and synaptic glutamate transmission in both subdivisions of the NAc, to our knowledge, none have specified NAcSh D1R + MSNs from mice during pre- and mid-adolescence. METHODS: Sagittal brain slices containing the NAc were prepared from B6.Cg-Tg(Drd1a-tdTomato)6Calak/J mice of both sexes from postnatal days 21-25 and 35-47, representing pre- and mid-adolescence, respectively. Whole-cell electrophysiology recordings were collected from NAcSh D1R + MSNs in the form of membrane-voltage responses to current injections, to assess membrane properties and action potential waveform characteristics, and spontaneous excitatory postsynaptic currents (sEPSCs) to assess glutamatergic synaptic activity. RESULTS: Relative to pre-adolescent males, pre-adolescent female NAcSh D1R + MSNs exhibited a less hyperpolarized resting membrane potential, increased input resistance, and smaller action potential afterhyperpolarization amplitudes. During mid-adolescence, decreased input resistance and a shorter action potential duration in females were the only sex differences observed. CONCLUSIONS: Taken together, our results indicate that NAcSh D1R + MSNs in mice exhibit sex differences in membrane properties and AP waveform during pre-adolescence that are overall indicative of increased cellular excitability in females and are suggestive of possible sex differences in glycine receptors, inwardly-rectifying potassium channels, and large conductance voltage-gated potassium channels. These differences do not appear to persist into mid-adolescence, when sex was observed to affect input resistance oppositely to that of pre-adolescence and AP waveform in a manner suggestive of differences in voltage-gated potassium channels.

Adolescence marks a period of substantial changes in both the mind and body, where alterations in the brain's structure can influence behavior. One change in behavior exhibited by many adolescents is an increased tendency to take risks, particularly in males. While taking risks can result in positive outcomes, like learning new skills, it can also lead to reckless behaviors that may result in negative outcomes. The nucleus accumbens, a brain region tied to risk-taking and reward perception, is not well-studied during the transition from childhood to adulthood, particularly in terms of sex differences. To fill this gap in understanding, this study examined a specific type of brain cell in the nucleus accumbens of pre- and mid-adolescent male and female mice. We measured the electrical properties of these cells and assessed how they responded to manipulation of their electrical state. We also measured how much and how often excitatory electrical information is sent to these cells from other brain regions. Our results suggest that in pre-adolescent females, these brain cells are more excited by manipulations of their electrical state and that these brain cells in mid-adolescent males may take longer to communicate information to other brain regions than in similarly aged females. Understanding these intricacies of brain cell communication sheds light on potential sex-specific vulnerabilities during the transition from childhood to adulthood.