Dorsal Lateral Septum Mediates Acute Stress-Induced Analgesia through Downstream Lateral Hypothalamic Area Neurons

Core Concepts

The dorsal lateral septum (dLS) plays a key role in transforming acute stress induced by physical restraint into analgesia through its inhibitory projections to the excitatory neurons in the lateral hypothalamic area (LHA), which in turn modulate pain processing in the rostral ventromedial medulla.

Abstract

The study investigates the neural mechanisms underlying stress-induced analgesia (SIA), where acute stress can lead to the suppression of pain perception. The researchers found that the dorsal lateral septum (dLS) plays a crucial role in this process.
Key findings:

Activation of inhibitory dLS neurons is sufficient to induce analgesia, while silencing them blocks stress-induced analgesia.
dLS neurons synapse onto excitatory neurons in the lateral hypothalamic area (LHA), and this dLS→LHA pathway is required for SIA.
The dLS→LHA pathway is opioid-dependent and modulates pain processing through the pro-nociceptive neurons in the rostral ventromedial medulla (RVM).
dLS neurons are specifically recruited when the mice struggle to escape the physical restraint, and they inhibit the excitatory LHA neurons, leading to the disengagement of RVM neurons and suppression of nociception.
Fiber photometry recordings revealed that while dLS neurons are active throughout the struggle, the LHApost-dLS neurons are only transiently engaged at the onset of the struggle, suggesting they are inhibited by the dLS inputs.

In summary, the study delineates a polysynaptic pathway originating in the dLS that transforms the escape behavior under acute stress into analgesia by modulating the activity of downstream pain processing circuits.

Stats

The tail-flick latency was significantly increased in dLSGad67-hM3Dq mice after administration of the DREADD agonist DCZ compared to saline.
The number of licks and latency to lick on the hot-plate test were reduced in dLSGad67-hM3Dq mice after DCZ administration compared to saline.
Silencing dLS neurons with tetanus toxin abolished the stress-induced analgesia observed on the tail-flick and hot-plate tests.
Activation of the dLS→LHA pathway, either by optogenetic stimulation or chemogenetic activation, was sufficient to induce analgesia.
Silencing the LHApost-dLS neurons blocked the stress-induced analgesia.

Quotes

"Stress is a potent modulator of pain. Specifically, acute stress due to physical restraint induces stress-induced analgesia (SIA)."
"Remarkably, we found that the inhibitory dLS neurons are recruited specifically when the mice struggle to escape under restraint and, in turn, inhibit excitatory LHA neurons."
"Together, we delineate a poly-synaptic pathway that can transform escape behavior in mice under restraint to acute stress into analgesia."

Key Insights Distilled From

A septo-hypothalamic-medullary circuit directs stress-induced analgesia

by Barik,A., Sh... at www.biorxiv.org 02-02-2023

https://www.biorxiv.org/content/10.1101/2023.01.30.526171v4

Deeper Inquiries

How might the dLS-LHA-RVM circuit be involved in chronic pain conditions, and could targeting this pathway lead to novel therapeutic approaches

The dLS-LHA-RVM circuit is likely involved in chronic pain conditions through its role in modulating pain perception and stress responses. Chronic pain is often associated with alterations in the descending pain modulation pathways, including the dLS-LHA-RVM circuit. Dysregulation of this circuitry can lead to enhanced pain sensitivity and maladaptive responses to stress, contributing to the maintenance of chronic pain states. Targeting this pathway could offer novel therapeutic approaches for chronic pain management by modulating the activity of specific neural populations within the circuit. For example, interventions that enhance the inhibitory influence of dLS neurons on LHA and RVM neurons could potentially alleviate chronic pain symptoms by dampening pain signaling and promoting analgesia. Understanding the specific mechanisms by which this circuit contributes to chronic pain conditions could pave the way for the development of targeted interventions that address the underlying neural dysfunctions associated with persistent pain.

What other brain regions or neuromodulatory systems might interact with the dLS-LHA-RVM circuit to influence pain perception and stress responses

Several other brain regions and neuromodulatory systems are likely to interact with the dLS-LHA-RVM circuit to influence pain perception and stress responses. The periaqueductal gray (PAG), a key region involved in pain modulation, is known to receive inputs from both the LHA and RVM, forming a complex network that regulates pain processing. Additionally, the locus coeruleus (LC), a brainstem nucleus that releases norepinephrine, plays a crucial role in modulating pain sensitivity and stress responses. The LC projects to the dLS, LHA, and RVM, suggesting potential interactions with the dLS-LHA-RVM circuit. Serotonergic pathways originating from the raphe nuclei and dopaminergic projections from the ventral tegmental area (VTA) may also influence the activity of the dLS-LHA-RVM circuit, contributing to the modulation of pain and stress responses. Furthermore, the endogenous opioid system, including the release of endorphins and enkephalins, interacts with the RVM and plays a significant role in pain modulation and stress-induced analgesia.

Could the insights from this study on the neural mechanisms of stress-induced analgesia provide clues about the evolutionary origins and adaptive significance of this phenomenon

Insights from this study on the neural mechanisms of stress-induced analgesia provide valuable clues about the evolutionary origins and adaptive significance of this phenomenon. Stress-induced analgesia is a conserved response observed across various species, suggesting its evolutionary importance in promoting survival. The dLS-LHA-RVM circuit likely evolved to enable rapid and adaptive responses to acute stressors, such as escaping from predators or dangerous situations. By suppressing pain perception during stressful events, animals can focus on survival behaviors without being hindered by nociceptive signals. This adaptive mechanism allows for the prioritization of immediate threats over ongoing pain sensations, enhancing the chances of survival in challenging environments. The intricate interplay between stress, pain, and the neural circuitry involved in stress-induced analgesia highlights the evolutionary significance of these adaptive responses in ensuring the organism's survival and well-being.