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The Habenula: From Synaptic Dynamics to Mood Disorders

The Shabel Lab is at the forefront of investigating the role of the habenula in motivated behavior and mood disorders. Their pioneering work includes devising the first behavioral test for pessimism and utilizing techniques such as endoscopic imaging and habenula activity perturbation to uncover the neuronal mechanisms underlying pessimism in rodents. Moreover, they employ single-cell transcriptomics to elucidate molecular alterations in the human habenula associated with depression.

The lab’s ultimate goal is to pinpoint specific classes of habenula neurons implicated in pessimism and depression and identify potential molecular targets for novel antidepressant therapies. “By bridging the rodent and human habenula with single-cell transcriptomics, we hope to translate our findings from rodents to humans, and vice versa, to understand how the habenula goes awry in mood disorders,” said Steven Shabel, Ph.D., an Assistant Professor of Psychiatry and Neuroscience and an Investigator in the Peter O’Donnell Jr. Brain Institute at UT Southwestern Medical Center.

In recent studies, it was discovered that in animals exhibiting depressive symptoms, the habenula displayed heightened synaptic potentiation, a phenomenon associated with increased excitability. This observation, coupled with findings in primates indicating habenular activation in response to adverse events, sparked curiosity regarding the role of the habenula in depression.

Of particular interest was a projection to the habenula from the globus pallidus, implicated in reward prediction error computations. This led to an exploration of isolating this specific pathway in brain slices to investigate its transmission dynamics. Leveraging optogenetics, the researchers could selectively stimulate this projection, revealing it to be excitatory, contrary to previous assumptions. This discovery opened new avenues for understanding the intricate circuitry of the habenula.

Further investigations unveiled a surprising phenomenon: the co-release of GABA, an inhibitory neurotransmitter, alongside glutamate, the primary excitatory neurotransmitter in this projection. Such simultaneous release was unusual, especially given the scarcity of GABAergic interneurons in the habenula. Extensive experimentation confirmed this co-release phenomenon, marking a significant breakthrough in understanding synaptic transmission within the habenula.

The implications of these findings extend beyond synaptic physiology, potentially influencing depressive behaviors. Alterations in the excitatory-inhibitory balance within the habenula may contribute to the dysregulation observed in depression. Moreover, the interplay between neurotransmitter release and reward computations adds complexity to our understanding of habenular function. “Excitatory-inhibitory balance at individual synapses in the habenula may determine how strongly aversive and rewarding experiences affect us,” Dr. Shabel explained.

While acknowledging these advancements, fundamental questions persist and await further exploration. The precise mechanisms driving co-release and its relevance to pessimism and depressive pathology require further exploration. Current efforts focus on genetically manipulating this co-release phenomenon in animal models to dissect its impact on habenular activity and depressive behaviors.

Research from the Shabel Lab illuminates the role of the habenula in mood disorders. By exploring neuronal circuits and neurotransmitter dynamics, lab members aim to innovate therapeutic interventions for depression and related mood disorders. Their findings not only deepen our understanding of depressive pathology, but also open new pathways for developing more effective treatments.

Visit Dr. Shabel’s profile to delve deeper into his research and explore the ongoing work of his laboratory.