Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective

Abstract

Adverse events and childhood trauma increase the susceptibility towards developing psychiatric disorders (substance use disorder, anxiety, depression, etc.) in adulthood. Although there are treatment strategies that have utility in combating these psychiatric disorders, little attention is placed on how to therapeutically intervene in children exposed to early life stress (ELS) to prevent the development of later psychopathology. The lateral habenula (LHb) has been a topic of extensive investigation in mental health disorders due to its prominent role in emotion and mood regulation through modulation of brain reward and motivational neural circuits. Importantly, rodent models of ELS have been shown to promote LHb dysfunction. Moreover, one of the potential mechanisms contributing to LHb neuronal and synaptic dysfunction involves endocannabinoid (eCB) signaling, which has been observed to critically regulate emotion/mood and motivation. Many pre-clinical studies targeting eCB signaling suggest that this neuromodulatory system could be exploited as an intervention therapy to halt maladaptive processes that promote dysfunction in reward and motivational neural circuits involving the LHb. In this perspective article, we report what is currently known about the role of eCB signaling in LHb function and discuss our opinions on new research directions to determine whether the eCB system is a potentially attractive therapeutic intervention for the prevention and/or treatment of ELS-associated psychiatric illnesses.

Lateral Habenula Beyond Avoidance: Roles in Stress, Memory, and Decision-Making With Implications for Psychiatric Disorders

“…Several neural pathways and neurobiological mechanisms such as the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic corticotropin-releasing factor (CRF) circuits have been identified by which ELS may increase the risk for mood dysregulation, stress-related disorders and addiction (Nemeroff, 2016). Emerging evidence now suggests that ELS-induced alterations of reward-and stress-related brain regions such as ventral tegmental area (VTA), amygdala, nucleus accumbens, prefrontal cortex and LHb may underlie the increased risk for ELS-induced psychopathology (Authement et al, 2015(Authement et al, , 2018Peña et al, 2017Peña et al, , 2019Tchenio et al, 2017;Bolton et al, 2018a;Simmons et al, 2020;Langlois et al, 2021;Oh et al, 2021;Shepard and Nugent, 2021). Specifically, recent studies provided compelling evidence that the LHb is a critical converging brain region for ELS-induced dysregulation of reward circuits (Tchenio et al, 2017;Authement et al, 2018;Bolton et al, 2018b;Simmons et al, 2020).…”

“…Across these diverse types of memory and cognitive processing, a fundamental contribution of the LHb may be to constantly monitor one's current internal state relative to external environmental conditions so that behaviors can be modified as needed (Baker et al, 2015;Lecca et al, 2020). Such a contribution appears to rely on the integration and signaling of cognitive, motivational/emotional, and behavioral state information (Sutherland, 1982;Chastrette et al, 1991;Nair et al, 2013;Mendoza, 2017;Shepard and Nugent, 2021). For example, LHb responds to positive and negative choice outcomes (Matsumoto and Hikosaka, 2009;Li et al, 2019), the generation of prediction error signals (Hong and Hikosaka, 2013;Tian and Uchida, 2015), changes in motivational and physiological states [e.g., stress, time of day, etc., (Shepard et al, 2018b;Salaberry et al, 2019;Langlois et al, 2021)], and changes in behavioral state (Baker et al, 2015;Nuno-Perez et al, 2018;Lecca et al, 2020).…”

Inhibition Within the Lateral Habenula—Implications for Affective Disorders

“…Other recent work has pointed to the role of endocannabinoid signalling in modulating LHb function (Shepard and Nugent, 2021). CB1 receptor activation has been shown to reduce inhibitory synaptic input onto LHb neurons (Authement et al, 2018), while at the behavioural level, intra-LHb infusion of ∆9tetrahydrocannabinol has been shown to induce a deficit in impulsivity control in rats (Zapata and Lupica, 2021).…”

The Role of the Lateral Habenula in Suicide: A Call for Further Exploration

“…A further specification of the effect of monoamine theories of suicide relates to the endocannabinoid (eCB) system in the LHb. The eCB system consists of receptors, receptor agonists, and classified as lipid mediators and receptors are typically situated in the presynaptic terminal of the neuron, meaning they are synthesized in an activity-dependent manner compared to neurotransmitters (Shepard and Nugent, 2021 ). Dysregulation of the eCB system has been implicated in neuropsychiatric conditions, including depression and other stress-related disorders (Castillo et al, 2012 ; Berger et al, 2018 ).…”

“…The eCB system interacts with other neuromodulatory systems and may thus represent an extension of the monoamine theory of depression, as it regulates the release of glutamate, GABA, and other monoamines implicated in depression (Castillo et al, 2012 ). Notably in the LHb, eCB signaling plays a role in controlling synaptic plasticity, neuronal activity, and subsequent associated behavior, therefore alterations in eCB regulation of LHb neurons contribute to LHb dysfunction that is associated with motivational and social deficits seen in depression and stress-related disorders (Shepard and Nugent, 2021 ). In the Fluid Vulnerability Theory of suicide, eCB levels in the LHb could then play a crucial role in understanding biological predispositions to suicide risk, which then could be compounded by chronic stress (Authement et al, 2018 ).…”