Probes for PARVALBUMIN

Parvalbumin (PV) expressing GABAergic interneurons provide large source of GABA to spiny projection neurons (SPNs) in the striatum. However, the roles of PV+ interneurons in the regulation of SPNs in the ventral striatum and emotional states are largely unknown. Here, we investigated whether stimulation of ventral striatal (accumbal) PV+ interneurons would drive emotional valence in mice. We found that during conditioned place preference (CPP) training, activation of accumbal PV+ interneurons evoked place preference while suppressing them resulted in conditioned place aversion (CPA). Activation of PV+interneurons during place conditioning increased Fos expression in SPNs in the direct pathway (dSPNs) and impaired lithium chloride-induced CPA. Activation of dSPNs and SPNs in the indirect pathway (iSPNs) induced CPP and CPA, respectively; conversely, suppression of dSPNs or iSPNs induced CPA or CPP. In addition, activation or suppression of calretinin-expressing (CR) GABAergic interneurons did not induce place preference or aversion. These data suggest that PV+ interneurons can bidirectionally determine the emotional valence through their regulation of accumbal SPN activities and raise the possibility that manipulation of PV+ interneuron activity may have the potential to alter emotional valence and treat related mental disorders.

Background Aging is accompanied by altered thinking (cognition) and feeling (mood), functions that depend on information processing by brain cortical cell microcircuits. We hypothesized that age-associated long-term functional and biological changes are mediated by gene transcriptomic changes within neuronal cell-types forming cortical microcircuits, namely excitatory pyramidal cells (PYC) and inhibitory GABAergic neurons expressing vasoactive intestinal peptide (Vip), somatostatin (Sst) and parvalbumin (Pvalb). Methods To test this hypothesis, we assessed locomotor, anxiety-like and cognitive behavioral changes between young (2 months, n=9) and old (22 months, n=12) male C57BL/6 mice, and performed frontal cortex cell-type specific molecular profiling, using laser-capture microscopy and RNA sequencing. Results were analyzed by neuroinformatics and validated by fluorescent in situ hybridization. Results Old-mice displayed increased anxiety and reduced working memory. The four cell-types displayed distinct age-related transcriptomes and biological pathway profiles, affecting metabolic and cell signaling pathways, and selective markers of neuronal vulnerability (Ryr3), resilience (Oxr1), and mitochondrial dynamics (Opa1), suggesting high age-related vulnerability of PYCs, and variable degree of adaptation in GABAergic neurons. Correlations between gene expression and behaviors suggest that changes in cognition and anxiety associated with age are partly mediated by normal age-related cell changes, and that additional age-independent decreases in synaptic and signaling pathways, notably in PYC and SST-neurons further contribute to behavioral changes. Conclusions Our study demonstrates cell-dependent differential vulnerability and coordinated cell-specific cortical microcircuit molecular changes with age. Collectively, the results suggest intrinsic molecular links between aging, cognition and mood-related behaviors with SST-neurons contributing evenly to both behavioral conditions.

By virtue of their extensive axonal arborisation and perisomatic synaptic targeting, cortical inhibitory Parvalbumin (PV) cells strongly regulate principal cell output and plasticity and modulate experience-dependent refinement of cortical circuits during development. An interesting aspect of PV cell connectivity is its prolonged maturation time course, which is completed only by end of adolescence. The p75 neurotrophin receptor (p75NTR) regulates numerous cellular functions, however its role on cortical circuit development and plasticity remains elusive, mainly because localizing p75NTR expression with cellular and temporal resolution has been challenging.By using RNAscope and a modified version of the Proximity Ligation Assay, we found that p75NTR expression in PV cells decreases between the second and fourth postnatal week, at a time when PV cell synapse numbers increase dramatically. Conditional knockout of p75NTR in single PV neurons in vitro and in PV cell networks in vivo causes precocious formation of PV cell perisomatic innervation and perineural nets around PV cell somata, therefore suggesting that p75NTR expression modulates the timing of maturation of PV cell connectivity in the adolescent cortex.Remarkably, we found that PV cells still express p75NTR in adult mouse cortex of both sexes and that its activation is sufficient to destabilize PV cell connectivity and to restore cortical plasticity following monocular deprivation in vivo. Altogether, our results show that p75NTR activation dynamically regulates PV cell connectivity, and represents a novel tool to foster brain plasticity in adults.SIGNIFICANCE STATEMENTIn the cortex, inhibitory, GABA-releasing neurons control the output and plasticity of excitatory neurons. Within this diverse group, parvalbumin-expressing (PV) cells form the larger inhibitory system. PV cell connectivity develops slowly, reaching maturity only at the end of adolescence, however the mechanisms controlling the timing of its maturation are not well understood. We discovered that the expression of the neurotrophin receptor p75NTR in PV cells inhibits the maturation of their connectivity in a cell autonomous fashion, both in vitro and in vivo and that p75NTR activation in adult PV cells promotes their remodelling and restores cortical plasticity. These results reveal a new p75NTR function in the regulation of the time course of PV cell maturation and in limiting cortical plasticity.