Disentangling neuronal inhibition and inhibitory pathways in the lateral habenula

Abstract

22 Phone: +44 (0)141 548 2122 23 24 2 25 Summary: The lateral habenula receives inhibitory input from three distinct sources: 26 from local PV-positive neurons, from PV-positive neurons in the medial dorsal thalamic 27 nucleus (MDT); and from SOM-positive neurons in the ventral pallidum (VP). 28 3 Abstract 29 The lateral habenula (LHb) is hyperactive in depression, and thus potentiating 30 inhibition of this structure makes an interesting target for future antidepressant 31 therapies. However, the circuit mechanisms mediating inhibitory signalling within the 32 LHb are not well-known. We addressed this issue by studying LHb neurons expressing 33 either parvalbumin (PV), neuron-derived neurotrophic factor (Ndnf) or somatostatin 34 (SOM), three markers of particular sub-classes of neocortical inhibitory neurons. While 35 we report that Ndnf is not representative of any particular sub-population of LHb 36 neuron, we find that both PV and SOM are expressed by physiologically distinct sub-37 classes. Furthermore, we describe multiple sources of inhibitory input to the LHb 38 arising from both local PV-positive neurons, and from PV-positive neurons in the 39 medial dorsal thalamic nucleus, and from SOM-positive neurons in the ventral 40 pallidum. These findings hence provide new insight into inhibitory control within the 41 LHb, and highlight that this structure is more neuronally diverse than previously 42 thought. 43 44Significance statement 45 The circuitry by which inhibitory signalling is processed within the lateral habenula is 46 currently not well understood; yet this is an important topic as inhibition of the lateral 47 53We are grateful to Hongkui Zeng from the Allen Brain Institute, Seattle, for kindly 54 sharing the Ai9 reporter mice with us, and we thank Csaba Földy, Brain Research 55

NDNF is selectively expressed by neocortical, but not habenular neurogliaform cells

“…Several reports have recently proposed the existence of locally targeting GABAergic neurons within the LHb (Flanigan et al., 2020; Webster et al., 2020; Zhang et al., 2018). Earlier work has also indicated that a subclass of neuron physiologically and morphologically akin to that of neurogliaform cells exists within the LHb (Wagner et al., 2016; Weiss & Veh, 2011), although as‐of‐yet no evidence exists to indicate that these form functional local connections.…”

Early-life experiences altered the maturation of the lateral habenula in mouse models, resulting in behavioural disorders in adulthood

“…Although about 80% of PV neurons in the lateral habenula were surrounded by PNNs (Appendix 1, Figure S1F and G), more than 40% are GABA-negative and express little GAD1 and GAD2 (Appendix 1, Figure S1C, D, E and G). Webster and colleagues 35 have reported finding GABApositive and glutamatergic PV neurons, whose optogenetic activation elicited inhibitory and excitatory responses in the lateral habenula. That study and the present study showed that PV neurons in the lateral habenula are a heterogeneous population consisting of GABAergic and glutamatergic neurons; therefore, the roles of the PV neurons in the lateral habenula are thought to be different from in the cortex.…”

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Modulate the Anesthetic Potency of Isoflurane in Mice

“…This study contains some limitations. Although LHb neurons are predominantly glutamatergic [40], a small subset express glutamic acid decarboxylase 2 [41][42][43], which is recognized as a GABA marker. Neurons in the LHb respond differently to the activation of LHA glutamatergic neurons [16].…”