Abstract
Clinical and preclinical evidence implicates hyperexcitability of the lateral habenula (LHb) in the development of psychiatric disorders including major depressive disorder (MDD). This discrete epithalamic nucleus acts as a relay hub linking forebrain limbic structures with midbrain aminergic centers. Central to reward processing, learning and goal directed behavior, the LHb has emerged as a critical regulator of the behaviors that are impaired in depression. Stress-induced activation of the LHb produces depressive- and anxiety-like behaviors, anhedonia and aversion in preclinical studies. Moreover, deep brain stimulation of the LHb in humans has been shown to alleviate chronic unremitting depression in treatment resistant depression. The diverse neurochemical processes arising in the LHb that underscore the emergence and treatment of MDD are considered in this review, including recent optogenetic studies that probe the anatomical connections of the LHb.
Highlights
Distinct physiological and molecular activity in a small region located in the most caudal and distal part of the epithalamus, known as the habenula, regulates circuit based alterations associated with the progression of depression in humans (Sartorius et al, 2010) and depressive-like behavior in rodents (Shabel et al, 2014)
The studies covered in this review provide evidence in support of the lateral habenula (LHb) hyperexcitability in the development and remediation of depression, more work is needed to consolidate this hypothesis
The use of Designer Receptor Exclusively Activated by Designer Drug (DREADD) technology (Nair et al, 2013) has produced some exciting information pertaining to LHb circuits relevant to depression, aversion, motivation and stress reactivity
Summary
Distinct physiological and molecular activity in a small region located in the most caudal and distal part of the epithalamus, known as the habenula, regulates circuit based alterations associated with the progression of depression in humans (Sartorius et al, 2010) and depressive-like behavior in rodents (Shabel et al, 2014). Pathway analysis of a microarray conducted on LHb samples collected from CMS exposed escitalopram nonresponder and responder rats, revealed that recovery of stressinduced behavioral deficits was dependent on the restoration of growth factor receptor signaling for VEGF and EGF, histamine H1 receptor signaling, oxytocin receptor mediated signaling, Wnt signaling, glutamine glutamate conversion and transcription regulation by bZIP (Christensen et al, 2013), which is typically required for transcription factors such as cAMP response element-binding protein (CREB) to initiate transcription of neurotropic factors and neuropeptides like CRF and endogenous opioids In line with these findings, early-life stress in the form of maternal deprivation (MD) increased LHb intrinsic excitability in adolescent rats, associated with significant reduction in medium afterhyperpolarization (mAHP) amplitude and higher input resistance (Authement et al, 2018).
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