Biology subjects

Dao, N. C.

Publications and source records attributed to Dao, N. C..

6 recordsLinked to original sources

bioRxiv2022

Adolescent binge drinking leads to long lasting changes in cortical microcircuits

Adolescent drug consumption has increased risks to the individual compared to consumption in adulthood, due to the likelihood of long-term and permanent behavioral and neurological adaptations. However, little is known about how adolescent alcohol consumption influences the maturation and trajectory of cortical circuit development. Here, we explore the consequences of adolescent binge drinking on somatostatin (SST) neuronal function in superficial layers of the prelimbic (PL) cortex in male and female SST-Ai9 mice. We find that adolescent drinking-in-the-dark (DID) produces sex-dependent increases in intrinsic excitability of SST neurons, with no change in overall SST cell number, persisting well into adulthood. While we did not find evidence of altered GABA release from SST neurons onto other neurons within the circuit, we found a complementary reduction in layer II/III pyramidal neuron excitability immediately after binge drinking; however, this hypoexcitability rebounded towards increased pyramidal neuron activity in adulthood in females, suggesting long-term homeostatic adaptations in this circuit. Together, this suggests that binge drinking during key developmental timepoints leads to permanent changes in PL microcircuitry function, which may have broad behavioral implications.

neuroscience↗

bioRxiv2022

Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior

Somatostatin (SST) neurons in the prelimbic (PL) cortex mediate a variety of behavioral states. However, little is known about the actions of somatostatin peptide signaling in shaping cortical functioning and behavior. Here, we sought to characterize the unique physiological and behavioral roles of the SST peptide in the PL cortex. We employed a combination of ex vivo pharmacologic and optogenetic electrophysiology, in vivo calcium monitoring, and in vivo peptide pharmacology to explore the role of SST neuron and peptide signaling in the mouse PL cortex. Whole-cell slice electrophysiology was conducted in pyramidal and GABAergic neurons in the PL cortex of C57BL/6J and SST-IRES-Cre male and female mice to characterize the pharmacological mechanism of SST signaling. Fiber photometry of GCaMP6f fluorescent calcium signals from SST neurons was conducted to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field test (OFT). We further used local delivery of both a broad SST receptor (SSTR) agonist and antagonist into bilateral PL cortex to test causal effects of SST administration and receptor blockade on these same exploratory behaviors. SSTR activation broadly hyperpolarized layer 2/3 pyramidal neurons in the PL cortex in both male and female mice ex vivo, an effect that was recapitulated with optogenetic stimulation of SST neurons, through both monosynaptic and polysynaptic GABA neuron-mediated mechanisms of action. This hyperpolarization was blocked by pre-application of the SSTR antagonist cyclo-somatostatin (cyclo-SST) and was non-reversible. SST neurons in PL were activated during EPM and OFT exploration, indicating task-related recruitment of these neurons. Lastly, in line with this exploration-related activity profile, SSTR agonist administration directly into the PL enhanced open arm exploration in the EPM, while in vivo administration of an antagonist had no effect. Together, this work describes a broad ability for SST peptide signaling to modulate microcircuits within the prefrontal cortex and related exploratory behaviors.

neuroscience↗

bioRxiv2022

Somatostatin Neurons in the Bed Nucleus of the Stria Terminalis Play a Sex-Dependent Role in Binge Drinking

Alcohol use disorder (AUD) is characterized by alcohol use coupled with chronic relapse and involves brain regions including the bed nucleus of the stria terminalis (BNST). Here, we explore whether a subpopulation of BNST neurons, somatostatin (SST) expressing GABAergic neurons, play a role in an animal model of binge-like alcohol consumption, the Drinking in the Dark (DID) model. Chemogenetic activation of BNST SST neurons reduced binge alcohol consumption in female but not male SST-Cre mice, while inhibition of these neurons in the same mice had no effect. In addition, chemogenetic activation of these neurons did not cause apparent changes in models of anxiety-like behavior in either sex. Basal SST cell counts and intrinsic excitability of SST neurons were compared to attempt to understand sex differences in DREADD-induced changes in drinking, and while males had a greater number of BNST SST neurons, this effect went away when normalizing for total BNST volume. Together, these results suggest SST neurons in the BNST should be further explored as a potential neuronal subtype modulated by AUD, and for their therapeutic potential. HIGHLIGHTSO_LIChemogenetic activation of BNST SST neurons reduces binge drinking in female but not male mice C_LIO_LIChemogenetic activation of these neurons has no effect on anxiety-like behavior in either sex C_LIO_LIElectrophysiology revealed no clear sex differences in intrinsic excitability BNST SST neurons between males and females C_LIO_LIImaging revealed males had greater overall BNST SST cell numbers than females, but this effect could be explained by normalizing for total BNST volume C_LI

neuroscience↗

bioRxiv2020

Bi-directional control of a prelimbic somatostatin microcircuit decreases binge alcohol consumption

Somatostatin neurons have been implicated in a variety of neuropsychiatric disorders such as depression and anxiety, but their role in substance abuse disorders, including alcohol use disorder (AUD), is not fully characterized. Here we found that repeat cycles of alcohol binge drinking in the Drinking-in-the-Dark (DID) model led to hypoactivity of somatostatin (SST) neuronal in the prelimbic (PL) cortex by diminishing their action potential firing capacity and excitatory/inhibitory transmission dynamic. We examined their role in regulating alcohol consumption via bidirectional chemogenetic manipulation. Both hM3Dq-induced excitation and KORD-induced silencing of PL SST neurons paradoxically reduced alcohol binge drinking in males and females, with no effect on sucrose consumption. This effect is mediated directly via monosynaptic connection from SST neurons onto pyramidal neurons and indirectly via an intermediate GABAergic source. Optogenetic-assisted circuit mapping revealed that PL SST neurons preferentially synapse onto pyramidal neurons over other GABAergic populations in males, whereas SST neuron-mediated inhibition is balanced across cell types in females. Alcohol binge drinking disinhibits pyramidal neurons by augmenting SST neurons-mediated GABA release and synaptic strength onto other GABAergic populations. Together these data suggest substantial interaction between alcohol binge drinking and SST neurons inhibitory circuit in the PL, as well as provide evidence for these neurons as a potential therapeutic candidate for the treatment of alcohol use disorders, including binge drinking.

neuroscience↗

bioRxiv2020

Forced Abstinence from Alcohol Induces Sex-Specific Depression-like Behavioral and Neural Adaptations in Somatostatin Neurons in Cortical and Amygdalar Regions

Forced abstinence (FA) from alcohol has been shown to produce a variety of anxiety- and depression- like symptoms in animal models. Somatostatin (SST) neurons, a subtype of GABAergic neurons found throughout the brain, are a novel neural target with potential treatment implications in affective disorders, yet their role in alcohol use disorders (AUD) remains to be explored. Here, we examined the neuroadaptations of SST neurons during forced abstinence from voluntary alcohol consumption. Following six weeks of two-bottle choice alcohol consumption and protracted forced abstinence, male and female C57BL/6J mice exhibited a heightened, but sex-specific, depressive-like behavioral profile in the sucrose preference test (SPT) and forced swim test (FST), without changes in anxiety-like behaviors in the elevated plus maze (EPM) and open field test (OFT). FST-induced cFos expressions in the prefrontal cortex (PFC) and ventral bed nucleus of the stria terminalis (vBNST) were altered in FA-exposed female mice only, suggesting a sex-specific effect of forced abstinence on the neural response to acute stress. SST immunoreactivity in these regions was unaffected by forced abstinence, while differences were seen in SST/cFos co-expression in the vBNST. No differences in cFos or SST immunoreactivity were seen in the lateral central nucleus of the amygdala (CEA) and the basolateral amygdala (BLA). Additionally, SST neurons displayed opposing alterations in the PFC and vBNST, with heightened intrinsic excitability in the PFC and diminished intrinsic excitability in the vBNST. These findings provide an overall framework of forced abstinence-induced neuroadaptations in these key brain regions involved in emotional regulation and processing.

neuroscience↗

bioRxiv2019

Novel characterization of peptidergic release from prefrontal cortical somatostatin neurons

Somatostatin is a neuropeptide thought to play a role in a variety of neuropsychiatric disorders, and is important for healthy aging and behavioral resiliency. Conditions governing somatostatin peptidergic release are not well-defined. Using a combination of optogenetic, transgenic, and biochemical approaches, we demonstrate an assay for the induction and inhibition of somatostatin in acute brain slices.

neuroscience↗