A GABAergic cell type in the lateral habenula links hypothalamic homeostatic and midbrain motivation circuits with sex steroid signaling

Abstract

The lateral habenula (LHb) has a key role in integrating a variety of neural circuits associated with reward and aversive behaviors. There is limited information about how the different cell types and neuronal circuits within the LHb coordinate physiological and motivational states. Here, we report a cell type in the medial division of the LHb (LHbM) in male rats that is distinguished by: (1) a molecular signature for GABAergic neurotransmission (Slc32a1/VGAT) and estrogen receptor (Esr1/ERα) expression, at both mRNA and protein levels, as well as the mRNA for vesicular glutamate transporter Slc17a6/VGLUT2, which we term the GABAergic estrogen-receptive neuron (GERN); (2) its axonal projection patterns, identified by in vivo juxtacellular labeling, to both local LHb and to midbrain modulatory systems; and (3) its somatic expression of receptors for vasopressin, serotonin and dopamine, and mRNA for orexin receptor 2. This cell type is anatomically located to receive afferents from midbrain reward (dopamine and serotonin) and hypothalamic water and energy homeostasis (vasopressin and orexin) circuits. These afferents shared the expression of estrogen synthase (aromatase) and VGLUT2, both in their somata and axon terminals. We demonstrate dynamic changes in LHbM VGAT+ cell density, dependent upon gonadal functional status, that closely correlate with motivational behavior in response to predator and forced swim stressors. The findings suggest that the homeostasis and reward-related glutamatergic convergent projecting pathways to LHbMC employ a localized neurosteroid signaling mechanism via axonal expression of aromatase, to act as a switch for GERN excitation/inhibition output prevalence, influencing depressive or motivated behavior.

Opposite responses to aversive stimuli in lateral habenula neurons

“…Therefore, any of these regions may drive Fs‐mediated inhibition. Another possibility is that a recently described population of GABAergic interneurons in the medial LHb promotes the inhibition after shock, although such functional connectivity remains to be demonstrated (Zhang, Hernández, Vázquez‐Juárez, Chay, & Barrio, ; Zhang, Hernánde, et al., ; Zhang, Shen, et al., ). Finally, the block of Fs‐excitation or Fs‐inhibition by pharmacological agents revealed pure excitatory or inhibitory responses.…”

“…Hypothalamic glutamatergic signal into the LHb is necessary to trigger LHb excitation and promotes innate escape behaviour (Lecca et al., ). Similarly, other glutamatergic inputs also drive aversive behaviours (Barker et al., ; Knowland et al., ; Shabel et al., ; Zhang, Hernánde, et al., ; Zhang, Shen, et al., ).…”

“…In contrast, the behavioural relevance of aversion‐driven GABA‐mediated inhibition in LHb cells remains unknown. Optogenetic activation of GABAergic terminals arising from different structures onto the LHb drives place preference (Barker et al., ; Root, Mejias‐Aponte, Qi, & Morales, ; Root, Mejias‐Aponte, Zhang, et al., ; Stamatakis et al., ; Zhang, Hernánde, et al., ; Zhang, Shen, et al., ). This is in line with a potential role of LHb inhibition in reward encoding (Matsumoto & Hikosaka, ).…”

Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior

“…Previous studies have described the LHb as consisting almost exclusively of glutamate projection neurons expressing vesicular glutamate transporter 2 (vGlut2) 21 . However, there is recent histological and single-cell sequencing evidence that the LHb contains a small population of cells that express glutamate decarboxylase 2 (GAD2) [22][23][24][25] , which is generally a marker of GABAergic inhibitory neurons. Despite these recent studies, very little is known about GAD2 neurons in the LHb, including which inputs target them or whether they are capable of providing local inhibition, long-range inhibition, or both.…”

“…Despite these recent studies, very little is known about GAD2 neurons in the LHb, including which inputs target them or whether they are capable of providing local inhibition, long-range inhibition, or both. Recent studies have reported that they are enriched in receptors for a number of hypothalamic-derived neuropeptides and hormones, including orexin receptor 2 (OxR2) 23,25 . As orexin neuron cell bodies are located solely in the lateral hypothalamus (LH) 26 , this suggests that LHb GAD2 neurons are modulated by projections from lateral hypothalamic orexin neurons.…”