Brad A. Grueter

Day length, or seasonal photoperiod, shapes mood and affective behaviors, but the neural mechanisms underlying these effects are still being defined. Serotonin neurons of the dorsal raphe nucleus (DRN) are critical regulators of affective behaviors, and photoperiod modulates their excitability and ongoing activity. Here, we investigated the influence of seasonal photoperiod on the function and expression of small conductance calcium‐activated potassium (SK) channels, which mediate the after‐hyperpolarizing potential (AHP) in dorsal raphe serotonin neurons. Building on previous work demonstrating that long summer‐like photoperiod increases serotonergic neuron excitability and decreases AHP amplitude, we hypothesized that day length influences SK channel activity, thereby contributing to differences in neuronal excitability observed between Long, Equinox, and Short photoperiod conditions. Using multielectrode array recordings from DRN slices, we found a significant, dose‐dependent increase in spike rate upon application of the SK channel inhibitor apamin, indicating that SK channels indeed influence the spike rate of dorsal raphe serotonin neurons. In addition, whole‐cell recordings from DRN neurons in slices demonstrated that SK channel–mediated AHP currents were smaller in amplitude in Long photoperiod mice compared to Short and Equinox photoperiod mice. However, we found no significant differences in mRNA levels of the SK3 subunit ( Kcnn3 ) in DRN serotonin neurons across photoperiod conditions as determined by single‐molecule fluorescence in situ hybridization. Overall, these findings indicate that photoperiod modulates SK channel function in DRN serotonin neurons, possibly through posttranscriptional mechanisms, contributing to the increase in serotonin neuron excitability observed in long summer‐like photoperiods.

Circular RNAs are backspliced, closed-loop RNAs previously believed to be noncoding by-products formed during transcription. Increasing evidence suggests that circular RNAs have crucial functions in the brain, such as regulating neuronal transmission and synaptic plasticity. However, the specific molecular mechanisms by which circular RNAs function remain largely unexplored. Here, we investigated how circHomer1 , a brain-enriched circular RNA derived from the Homer1 gene, affects hippocampus-dependent learning and memory. Our results demonstrate that circHomer1 plays a vital role in mediating the dendritic targeting of messenger RNAs that encode postsynaptic proteins by acting as a molecular bridge between the motor protein Kinesin 1 and core components of neuronal ribonucleoprotein granules, including Fused in Sarcoma and Fragile X Mental Retardation Protein, at dendrites. This interaction influences synaptic function, the structural morphology of dendritic spines, and hippocampus-dependent spatial learning and memory. Thus, our study highlights a role of circular RNAs in mediating synaptic messenger RNA targeting to shape dendritic spines and consequently neuronal functions.

Large-pore ion channels present a window of opportunity for cell-specific intracellular drug delivery. Here, we demonstrate that the capsaicin receptor, TRPV1, can be used for delivery of the membrane impermeant lidocaine derivative QX-314 into neurons in the brain in vivo by using drug-induced hyperlocomotion as a behavioral readout and we validated our findings with ex vivo electrophysiological recordings. Our studies present evidence that this strategy can be used to deliver membrane impermeant compounds in the brain.

Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid constituent of the cannabis plant that shows promise for the treatment of a variety of neuropsychiatric disorders such as anxiety disorders, post-traumatic stress disorder, and substance use disorders. The nucleus accumbens (NAc) is a key brain region in the etiologies of these disorders and is actively modulated by CBD. Prior research has established that CBD alters the molecular composition of the NAc, but none have assessed how CBD affects NAc neuronal function. In this study, we demonstrate that CBD significantly decreases D1 and D2 medium spiny neuron membrane excitability, broadens action potentials, and has no effect on spontaneous excitatory synaptic transmission in the NAc core. These data enhance our understanding of CBDs physiological effects and provide mechanistic insight into its therapeutic potential.

Interneuron populations within the nucleus accumbens (NAc) orchestrate excitatory-inhibitory balance, undergo experience-dependent plasticity, and gate-motivated behavior, all biobehavioral processes heavily modulated by endogenous cannabinoid (eCB) signaling. While eCBs are well known to regulate synaptic plasticity onto NAc medium spiny neurons and modulate NAc function at the behavioral level, how eCBs regulate NAc interneuron function is less well understood. Here, we show that eCB signaling differentially regulates glutamatergic and feedforward GABAergic transmission onto NAc somatostatin–expressing interneurons (NAc ^SOM+ ) in an input-specific manner, while simultaneously increasing postsynaptic excitability of NAc ^SOM+ neurons, ultimately biasing toward vHPC (ventral hippocampal), and away from BLA (basolateral amygdalalar), activation of NAc ^SOM+ neurons. We further demonstrate that NAc ^SOM+ are activated by stress in vivo and undergo stress-dependent plasticity, evident as a global increase in intrinsic excitability and an increase in excitation–inhibition balance specifically at vHPC, but not BLA, inputs onto NAc ^SOM+ neurons. Importantly, both forms of stress-induced plasticity are dependent on eCB signaling at cannabinoid type 1 receptors. These findings reveal eCB-dependent mechanisms that sculpt afferent input and excitability of NAc ^SOM+ neurons and demonstrate a key role for eCB signaling in stress-induced plasticity of NAc ^SOM+ -associated circuits.

The nucleus accumbens (NAc) guides reward-related motivated behavior implicated in pathological behavioral states, including addiction and depression. These behaviors depend on the precise neuromodulatory actions of G_i/o-coupled G-protein-coupled receptors (GPCRs) at glutamatergic synapses onto medium spiny projection neurons (MSNs). Previous work has shown that discrete classes of G_i/o-coupled GPCR mobilize Gβγ to inhibit vesicular neurotransmitter release via t-SNARE protein, SNAP25. However, it remains unknown which Gαi/o systems in the NAc utilize Gβγ-SNARE signaling to dampen glutamatergic transmission. Utilizing patch-clamp electrophysiology and pharmacology in a transgenic mouse line with a C-terminal three-residue deletion of SNAP25 (SNAP25Δ3) weaking the Gβγ-SNARE interaction, we surveyed a broad cohort of G_i/o-coupled GPCRs with robust inhibitory actions at glutamatergic synapses in the NAc. We find that basal presynaptic glutamate release probability is reduced in SNAP25Δ3 mice. While κ opioid, CB1, adenosine A1, group II metabotropic glutamate receptors, and histamine H3 receptors inhibit glutamatergic transmission onto MSNs independent of SNAP25, we report that SNAP25 contributes significantly to the actions of GABA_B, 5-HT1_B/D, and μ opioid receptors. These findings demonstrate that presynaptic G_i/o-coupled GPCRs recruit heterogenous effector mechanisms at glutamatergic synapses in the NAc, with a subset requiring SNA25-dependent Gβγ signaling.