Neural circuits and activity dynamics underlying sex-specific effects of chronic social isolation stress

Abstract

Exposure to prolonged stress in critical developmental periods induces heightened vulnerability to psychiatric disorders, which may have sex-specific consequences. Here we investigate the neuronal circuits mediating behavioral changes in mice after chronic adolescent social isolation stress. Escalated aggression is exhibited in stressed males, while social withdrawal is shown in stressed females. In vivo multichannel recordings of free-moving animals indicate that pyramidal neurons in prefrontal cortex (PFC) from stressed males exhibit the significantly decreased spike activity during aggressive attacks, while PFC pyramidal neurons from stressed females show a blunted increase of discharge rates during sociability tests. Chemogenetic and electrophysiological evidence shows that PFC hypofunctioning and BLA principal neuron hyperactivity contribute to the elevated aggression in stressed males, while PFC hypofunctioning and VTA dopamine neuron hypoactivity contribute to the diminished sociability in stressed females. These results establish a framework for understanding the circuit and physiological mechanisms underlying sex-specific divergent effects of stress.

Effects of footshock stress on social behavior and neuronal activation in the medial prefrontal cortex and amygdala of male and female mice

“…Among control vehicle-injected mice, females had more cFos+ cells in IL. Similar results were obtained by Tan et al who observed that pyramidal neurons in the mPFC of females after chronic adolescent social isolation stress showed a blunted increase of discharge rates during sociability tests [36]. Sex differences in the modulation of social behavior by the mPFC were previously explored regarding oxytocin-receptor-expressing interneurons which have differential responses to oxytocin in male and female mice and regulate the social motivation of female mice to interact with male mice during estrus [37].…”

Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model

“…We first measured the synaptic‐driven spontaneous action potentials (sAP) using a low Mg 2+ condition to enhance the activity of brain slices (Tan et al, 2021 ). As shown in Figure 3a,b , compared with age‐matched WT mice, sAP frequency of PFC pyramidal neurons was substantially lower in P301S mice (5–7 months old), which was significantly increased to the normal level by UNC0642 treatment (1 mg/kg, i.p., 3x) ( n = 15–18 cells, 3–5 mice/group, F 2,46 = 22.98, p < 0.0001, one‐way ANOVA).…”

“…Current‐clamp recording was performed to record action potential (AP) with intracellular solution (in mM: 100 K‐gluconate, 20 KCl, 10 HEPES, 4 ATP, 0.5 GTP, and 10 phosphocreatine, pH 7.3, 265–270 mOsm). To elevate basal neuronal activity, slices were perfused in a modified ACSF with low MgCl 2 (0.5 mM; Tan et al, 2021 ). For spontaneous AP (sAP) recording, a small current was injected to adjust the membrane potential to −60 mV.…”

“…To address this, we used a transgenic mouse model expressing human tau bearing P301S mutation, which develops filamentous tau lesions at 6 months of age (Yoshiyama et al, 2007 ; Zhang et al, 2014 ). Prefrontal cortex (PFC), a key target region of AD that is critical for high‐level cognitive function (Maillet & Rajah, 2013 ; Spellman et al, 2015 ; Tan et al, 2021 ; Yan & Rein, 2021 ), was focused. We discovered that euchromatic histone‐lysine N ‐methyltransferase 2 (EHMT2) was significantly elevated in PFC of P301S Tau mice, and inhibition of EHMT led to the amelioration of behavioral and synaptic deficits, as well as the normalization of large‐scale gene expression.…”

Striatal µ-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect

“…The frequency and amplitudes of sIPSCs were recorded under gap-free conditions for 3 min. Ih currents in SNc dopaminergic neurons were detected under whole-cell voltage-clamp mode (hold potential: -60 mV) using a series of voltage steps from -150 mV to 0 mV (1 sec, 30-mV increments) using the same internal and external solutions that were used for action potential recording (Tan et al, 2021). Thorlabs) delivered at 1-20 Hz with a 2-ms duration (10 pulses).…”