Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior

Abstract

A sudden aversive event produces escape behaviors, an innate response essential for survival in virtually all-animal species. Nuclei including the lateral habenula (LHb), the lateral hypothalamus (LH), and the midbrain are not only reciprocally connected, but also respond to negative events contributing to goal-directed behaviors. However, whether aversion encoding requires these neural circuits to ultimately prompt escape behaviors remains unclear. We observe that aversive stimuli, including foot-shocks, excite LHb neurons and promote escape behaviors in mice. The foot-shock-driven excitation within the LHb requires glutamatergic signaling from the LH, but not from the midbrain. This hypothalamic excitatory projection predominates over LHb neurons monosynaptically innervating aversion-encoding midbrain GABA cells. Finally, the selective chemogenetic silencing of the LH-to-LHb pathway impairs aversion-driven escape behaviors. These findings unveil a habenular neurocircuitry devoted to encode external threats and the consequent escape; a process that, if disrupted, may compromise the animal’s survival.

Opposite responses to aversive stimuli in lateral habenula neurons

“…Here we provide evidence for the existence of two neuronal populations in the LHb, both encoding aversive stimuli in an opposite fashion, namely via excitation or inhibition. Indeed, in this study, alongside with a previously characterized aversion‐excited population (Lecca et al., ; Matsumoto & Hikosaka, ; Trusel et al., ), we describe a territorially segregated, glutamate‐containing LHb neuronal subtype inhibited by Fs. Interestingly, in the anaesthetized mouse, these Fs‐inhibited cells preferentially fire more regularly and at a higher frequency (with a relatively rare occurrence of spikes in burst) compared to Fs‐excited neurons.…”

“…Interestingly, mapping the position of recorded neurons using post hoc histological analysis revealed that Fs‐inhibited cells were mainly located in the medial portion of the LHb (Figure e). In contrast, Fs‐excited neurons were found throughout the LHb without any apparent territorial preference (Lecca et al., ). Both inhibitory and excitatory responses to Fs shared similar properties including latency (Fs‐excited vs. Fs‐inhibited: 70.6 ± 8.38 ms vs. 77.08 ± 15.47 ms; Mann‐Whitney test, U = 593.5, p = 0.471) and duration (Fs‐excited vs. Fs‐inhibited: 145.2 ± 15.12 ms vs. 137.9 ± 16.98 ms; Mann‐Whitney test, U = 591, p = 0.46) of the response (Figure f).…”

“…Fs‐driven excitation of LHb neurons requires glutamatergic transmission from the lateral hypothalamus (Lecca et al., ). Yet, the exact contribution of the glutamatergic receptors subtype remains unexplored.…”

“…A double‐barrel pipette assembly (injection tip, <50 μm in diameter attached ~100 μm above the recording tip) was used for recording LHb spike activity with simultaneous local microinjection of drugs (Lecca et al., ). The injection pipette was filled with one of the following: CGP 54626 (100 μM), Picrotoxin (PTX, 0.5 μM), AP5 (100 μM) and NBQX (100 μM) (Lecca et al., ; Root, Mejias‐Aponte, Qi, & Morales, ; Root, Mejias‐Aponte, Zhang, et al., ). Drugs were microinjected into the LHb, using brief pulses of pneumatic pressure (40 psi, 40 ms, Picospritzer, IM‐300, Narishige, Japan).…”

“…Consistently, aversive stimuli including footshocks (Fs) predominantly recruit glutamatergic neurotransmission arising from several inputs (i.e. hypothalamus and/or entopeduncular nucleus; Shabel, Proulx, Trias, Murphy, & Malinow, ; Stephenson‐Jones et al., ; Barker et al., ) to excite LHb neurons (Lecca et al., ). Yet, aversion‐excited cells in the LHb represent only a portion of the entire neuronal population (Dong, Wilson, Skolnick, & Dafny, ; Gao, Hoffman, & Benabid, ; Lecca et al., ; Wang et al., ).…”