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Gene & Protein in Disease Orexin in depression

with earlier findings. DLK1-null mice exhibited reduced Although current in vitro studies have investigated the
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anxiety and depression levels, as indicated by the results of relationship between orexin and depression, researchers
the forced swim test (FST) and elevated plus maze, along have used several acute stress models, which can hamper
with increased locomotor activity, compared with those in the chronic and complex nature of human depression.
the control mice. These results indicate that DLK1 plays a Moreover, there is limited research on the translational
predominant role in depressive behavior through DLK1- potential, particularly how in vitro findings might inform
expressing orexin neurons. 41 the development of specific orexin receptor modulators as
therapeutic interventions for depression. Future research
The awakening and maintenance of the waking state should consider the chronic modulation of orexin activity
depend on the hypothalamus orexin system. The LH in depression models that mimic human pathophysiology
is integral to brain function and involved in substance for elucidating the relevance of these findings.
abuse. Neuroendocrine information pertaining to natural
rewards is consolidated by orexin neurons within the LH. 3. Orexin in animal models of depression
Drugs of abuse may exert their effects concurrently at the
LH and ventral tegmental area. The presence of rewards Recent studies have emphasized the role of orexin system
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or cues associated with them causes an elevation in c-Fos in regulating stress response and emotional behaviour,
expression and phospho-CREB levels within orexin making orexin an important hotspot in the animal models
neurons. OXA activates a G q/11 protein coupled–receptor of depression.
mediated phospholipase C (PLC)-diacylglycerol lipase Increased orexin signaling is associated with
(DAGL) enzymatic pathway in dopaminergic neurons in depression-like states, and pharmacological interventions
the ventral tegmental area, resulting in the production of targeting the orexin system can yield antidepressant-like
2-arachidonoylglycerol (2-AG) – an endocannabinoid effects. For instance, blocking orexin receptors in mice
(Figure 3). The 2-AG then inhibits GABAergic neurons by subjected to unpredictable chronic mild stress resulted
binding to cannabinoid receptor 1, which reduces GABA in substantial behavioral improvements, suggesting that
release. The process of glutamate binding to AMPA orexin antagonism counteracts stress-induced alterations
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and NMDA receptors might cause the disinhibition of in mood and behaviour; this finding is consistent with the
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dopaminergic neurons in the ventral tegmental area, notion that orexin signaling contributes to motivational
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where glutamate can enter dopaminergic neurons states, which can become dysregulated in depression. 51
through NMDA receptors and promote the activation of Motivation and stress are key factors in depression, with
PLC, further affecting the function of NMDA receptors orexin signaling systems modulating motivation and stress
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(Figure 6). This process subsequently allows orexin to responses. A previous study investigated the correlation
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regulate reward and incentive behaviors. between orexin and its receptors in brain regions related
The extensive projection of orexin neurons, ability to to depression by examining immobility in mice during
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sense an animal’s internal state, and high plasticity of signals FST. The analysis focused on the mRNA expression of
pertaining to natural rewards and drug abuse may be the orexin and its receptor concerning FST immobility. Results
primary factors for increased drug-seeking behaviour. indicated an inverse correlation between depressive
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Research indicates that mechanical stimulation (MS) of the behavior severity and hippocampal orexin expression,
ulnar nerve effectively reduces cocaine addiction behaviors along with elevated mRNA levels of orexin and its receptor
– an effect potentially associated with the orexinergic input in the amygdala. This unique relationship between the
from the LH to the lateral habenular nucleus (LHb). amygdala and hippocampus represents a neurobiological
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The axons of orexinergic neurons in the LH can directly motif appearing in depression, that is, the amygdala grows
extend and form synaptic connections, establishing direct in size and function, whereas the hippocampus shrinks. 53
synaptic contacts with neurons in the LHb. Systemically After stressful life experiences, there is an increased
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administering OX2R antagonists inhibited the activation risk of developing psychiatric illnesses, such as depression,
of LHb neurons by MS, and MS targeting the ulnar nerve anxiety, and posttraumatic syndrome, throughout
engaged an orexin LH-LHb pathway to dampen cocaine- adolescence, a sensitive and crucial time for brain
induced psychomotor responses. Hypothalamic neurons development. Individuals with these conditions exhibit
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are inhibited by opioids, which can reduce cognitive alterations in orexin levels. However, the exact function
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alertness and result in inhibiting orexin awakening system. of the orexin system in modulating these emotional
Exogenous opioids inhibit the orexin system through direct manifestations remains uncertain. The medial prefrontal
actions on the cell body, resulting in the development of cortex plays a role in emotional as well as cognitive
depression. 48 processing. Behavioral changes related to PTSD in

Volume 4 Issue 2 (2025) 7 doi: 10.36922/gpd.4210