Biology subjects

Birdsong, W. T.

Publications and source records attributed to Birdsong, W. T..

7 recordsLinked to original sources

bioRxiv2026

Human and Mouse Models of the Bipolar Disorder-Associated ANK3 p.W1989R Variant Display Altered Somatostatin Interneuron Connectivity and Function

Bipolar disorder (BD) is a debilitating neuropsychiatric disorder characterized by recurrent mood perturbations, cognitive and functional impairment, and increased risk of suicide. Genome-wide association studies (GWAS) have repeatedly identified the gene ANK3, which encodes the neuronal scaffolding protein ankyrin-G, as a risk locus for BD. Ankyrin-G interacts directly with the GABAA receptor-associated protein (GABARAP) to stabilize inhibitory synapses, providing a potential mechanistic link between ANK3 variation and GABAergic dysfunction observed in BD. Previously, we identified an ANK3 p.W1989R variant in a family with BD and demonstrated that this variant abolishes the ankyrin-G/GABARAP interaction, resulting in inhibitory signaling deficits in mice. Here, we investigated the effects of this variant in human induced pluripotent stem cell (hiPSC)-derived neurons generated from an affected individual heterozygous for the ANK3 p.W1989R variant. CRISPR correction of the variant increased inhibitory synapse density on both glutamatergic and GABAergic patient-derived neurons. Integrated spatial transcriptomics and calcium imaging identified cell-type-dependent changes in gene expression and calcium dynamics. ANK3 p.W1989R somatostatin (SST) positive interneurons displayed altered calcium dynamics and reduced SST expression. To determine whether the variant impacts SST interneuron-mediated inhibition of cortical circuits, we selectively stimulated prefrontal cortical SST interneurons in heterozygous Ank3 p.W1989R mice and recorded optically evoked inhibitory postsynaptic currents (oIPSCs) from cortical pyramidal neurons. SST interneuron-mediated oIPSC peak amplitude, charge transfer, and decay times were reduced in variant mice, without a significant change in the paired-pulse ratio. These findings, using complementary human and mouse models, identify novel roles for ankyrin-G in SST interneuron-mediated inhibitory signaling and demonstrate that altered inhibitory connectivity and SST interneuron function are associated with ANK3 p.W1989R. This work provides mechanistic insight into how disrupted ankyrin-G-dependent synaptic function may contribute to inhibitory signaling deficits relevant to BD.

neuroscience↗

bioRxiv2025

Delta Opioid Receptors on Parvalbumin Neurons are Necessary for the Convulsant and Anxiolytic Effects of the Delta Agonist SNC80

The delta opioid receptor (DOR) is expressed broadly throughout the central and peripheral nervous systems. Activation of DOR by exogenous and endogenous ligands regulates pain, motivation, emotion and memory, but the cells and neural circuits mediating these behavioral effects remain poorly characterized. Parvalbumin-expressing (PV) interneurons express high levels of DOR transcript (OPRD1) and protein (Birdsong et al 2019). Parvalbumin (PV) interneurons also play a role in pain and emotional processing, suggesting that DOR signaling on PV interneurons may modulate these behaviors. To address this question we used a conditional knockout mouse line (Floxed DOR; PV-cre) to delete DOR from PV-expressing cells. First, we validated the functional loss of DOR through whole-cell electrophysiology experiments. Next, we characterized baseline behavioral phenotypes and the convulsant, pro-locomotive and anxiolytic-like behavioral responses induced by the DOR agonist SNC80 in Floxed DOR; PV-Cre mice and their littermate controls. Interestingly, we found that the convulsant and anxiolytic effects of the DOR agonist SNC80 were diminished in Floxed DOR;PV Cre animals. However, baseline behavioral phenotypes, SNC80-induced spontaneous hyperlocomotion and respiratory stimulation were conserved. These novel findings indicate that the pro-convulsant and anxiolytic effects of DOR agonists are anatomically separable from the locomotor stimulating effects and are dependent on DOR expression on PV interneurons.

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bioRxiv2025

Excitatory synaptic transmission is differentially modulated by opioid receptors along the claustro-cingulate pathway

The anterior cingulate cortex (ACC) plays a pivotal role in processing pain and emotion, communicating with both cortical and subcortical regions involved in these functions. The claustrum (CLA), a subcortical region with extensive connectivity to the ACC also plays a critical role in pain perception and consciousness. Both ACC and CLA express Kappa (KOR), Mu (MOR), and Delta (DOR) opioid receptors, yet whether and how opioid receptors modulate this circuit is poorly understood. This study investigates the effects of opioid receptor activation on glutamatergic signaling in CLA-ACC circuitry using spatial transcriptomics, slice electrophysiology, optogenetics, and pharmacological approaches in mice. Our results demonstrated that excitatory inputs generated by the CLA onto layer 5 pyramidal cells (L5 PYR) in the ACC are reduced by KOR, MOR, and DOR agonists. However, only KOR agonists reduce monosynaptic transmission from the CLA onto L5 ACC PYR cells, highlighting the unique role of KOR in modulating the CLA-ACC pathway. MOR agonists had a heterogeneous effect on optically-evoked excitatory postsynaptic currents (oEPSCs), significantly reducing longer-latency excitatory responses while only modestly inhibiting the short latency excitatory postsynaptic currents. DOR agonists only reduce slower, longer-latency recurrent excitatory responses. These findings provide new insights into how opioid receptors regulate the claustro-cingulate circuit and demonstrate the distinct, receptor-specific modulation of synaptic transmission within this network.

neuroscience↗

bioRxiv2023

The Endogenous Opioid Met-Enkephalin Modulates Thalamo-Cortical Excitation Inhibition Balance in a Medial Thalamus-Anterior Cingulate Cortex Circuit

Activation of opioid receptors in the anterior cingulate cortex (ACC) mediates aspects of analgesia induced by both exogenous and endogenous opioids. We have previously shown that opioid signaling disrupts both afferent excitatory and indirect inhibitory synaptic transmission from the medial thalamus (MThal) to the ACC, but the effects of endogenous opioids within this circuit remain poorly understood. The goal of the current study was to understand how the endogenous opioid, [Met]5-enkephalin (ME), modulates thalamic-driven excitatory and inhibitory synaptic transmission onto layer V pyramidal neurons in the ACC. We used pharmacology, brain slice electrophysiology and optogenetic stimulation to study opioid-mediated modulation of optically evoked glutamatergic and GABAergic transmission. The results revealed that ME inhibited both AMPA-mediated excitatory and GABA-mediated inhibitory synaptic transmission in the ACC. However, inhibitory transmission was more potently inhibited than excitatory transmission by ME. This preferential reduction in GABAA-mediated synaptic transmission was primarily due to the activation of delta opioid receptors by ME and resulted in a net disinhibition of MThal-ACC excitatory pathway. These results suggest that moderate concentrations of ME can lead to net excitation of ACC circuitry and that analgesia may be associated with disinhibition rather than inhibition of ACC subcircuits.

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bioRxiv2023

Chronic morphine induces adaptations in opioid receptor signaling in a thalamo-cortico-striatal circuit that are projection-dependent, sex-specific and regulated by mu opioid receptor phosphorylation

Chronic opioid exposure induces tolerance to the pain-relieving effects of opioids but sensitization to some other effects. While the occurrence of these adaptations is well-understood, the underlying cellular mechanisms are less clear. This study aimed to determine how chronic treatment with morphine, a prototypical opioid agonist, induced adaptations to subsequent morphine signaling in different subcellular contexts. Opioids acutely inhibit glutamatergic transmission from medial thalamic (MThal) inputs to the dorsomedial striatum (DMS) and anterior cingulate cortex (ACC) via activity at -opioid receptors (MORs). MORs are present in somatic and presynaptic compartments of MThal neurons terminating in both the DMS and ACC. We investigated the effects of chronic morphine treatment on subsequent morphine signaling at MThal-DMS synapses, MThal-ACC synapses, and MThal cell bodies in male and female mice. Surprisingly, chronic morphine treatment increased subsequent morphine inhibition of MThal-DMS synaptic transmission (morphine facilitation), but decreased subsequent morphine inhibition of transmission at MThal-ACC synapses (morphine tolerance) in a sex-specific manner; these adaptations were present in male but not female mice. Additionally, these adaptations were not observed in knockin mice expressing phosphorylation-deficient MORs, suggesting a role of MOR phosphorylation in mediating both facilitation and tolerance to morphine within this circuit. The results of this study suggest that the effects of chronic morphine exposure are not ubiquitous; rather adaptations in MOR function may be determined by multiple factors such as subcellular receptor distribution, influence of local circuitry and sex.

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bioRxiv2021

Mu opioid receptors acutely regulate adenosine signaling in a thalamo-striatal circuit.

Endogenous adenosine plays a crucial role in maintaining energy homeostasis and adenosine levels are tightly regulated across neural circuits. In the dorsal medial striatum (DMS) adenosine inhibits neurotransmitter release, but the source and mechanism underlying its accumulation are largely unknown. Opioids also inhibit neurotransmitter release in the DMS and influences adenosine accumulation after prolonged exposure. However, how these two neurotransmitter systems interact acutely is also largely unknown. This study demonstrates that activation of opioid receptors (MORs), but not {delta} opioid receptors (DORs) or {kappa} opioid receptors (KORs), inhibits tonic activation of adenosine A1Rs via a cyclic adenosine monophosphate (cAMP) dependent mechanism in both male and female mice. Further, selectively knocking-out MORs from presynaptic terminals and postsynaptic medium spiny neurons (MSNs) revealed that activation of MORs on D1R positive MSNs, but not D2R positive MSNs, is necessary to inhibit tonic adenosine signaling on presynaptic terminals. Given the role of D1R positive MSNs in movement and motivated behaviors, these findings reveal a novel mechanism by which these neurons regulate their own synaptic inputs. Significance StatementUnderstanding interactions between neuromodulatory systems within brain circuits is a fundamental question in neuroscience. The present work uncovers a novel role of opioids in acutely inhibiting adenosine accumulation and subsequent adenosine receptor signaling in the striatum by inhibiting the production of cAMP. Adenosine receptor signaling regulates striatal neurotransmitters including glutamate, GABA, dopamine and acetylcholine. Furthermore, interactions between adenosine2A receptors and numerous other GPCRs, including D2 dopamine and CB1 cannabinoid receptors, suggest that endogenous adenosine broadly modulates striatal GPCR signaling. Additionally, this work discovered that resting endogenous adenosine is released by D1, but not D2 receptor positive MSNs, suggesting that opioid signaling and manipulation of D1R-expressing MSN cAMP activity can broadly affect striatal function and behavior.

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bioRxiv2019

Synapse-specific Opioid Modulation of Thalamo-cortico-striatal Circuits

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.

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