Differential Effects of the Lateral Hypothalamus Lesion as an Origin of Orexin and Blockade of Orexin-1 Receptor in the Orbitoftontal Cortex and Anterior Cingulate Cortex on Their Neuronal Activity

Several studies revealed that orexins may take part in the regulation of the different forms of affective and cognitive processes during wakefulness. The orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) as an important part of the prefrontal cortex (PFC) have a crucial role in cognitive processes such as reward and decision-making and has a high density of orexin receptor type 1 (OX1Rs). In the present study, to find out the role of OX1Rs in the OFC neurons firing rate, the OX1Rs were inhibited in this area after a10-min baseline recording. In the second part, the lateral hypothalamus (LH) as the main source of orexinergic neurons was inhibited and its effect on the firing rate and activity pattern of the ACC or OFC neurons were detected by using single-unit recording technique in the rats. Results showed that blockade of OX1Rs in the OFC could excite 8 and inhibit 1 neuron out of 11. Besides, the blockade of OX1Rs in the ACC could excite 6 and inhibit 3 neurons out of 10. Also, LH inactivation excited 5 out of 12 neurons and inhibited 6 neurons in the ACC. It excited 8 and inhibited 6 neurons out of 14 in the OFC. These data suggested that blockade of the OX1Rs excited 72% of the neurons, but LH inactivation had an exciting effect on just 50% of neurons in two main subregions of PFC. It seems that the PFC neurons receive the orexinergic inputs from the LH and indirectly from other sources.

From molecule to behavior: hypocretin/orexin revisited from a sex-dependent perspective

The hypocretin/orexin (Hcrt/Orx) system in the perifornical lateral hypothalamus has been recognized as a critical node in a complex network of neuronal systems controlling both physiology and behavior in vertebrates. Our understanding of the Hcrt/Orx system and its array of functions and actions have grown exponentially in merely two decades. This review will examine the latest progress in discerning the roles played by the Hcrt/Orx system in the regulation of homeostatic functions and in the execution of instinctive and learned behaviors. Furthermore, the gaps that currently exist in our knowledge of sex-related differences in this field of study are discussed.

Brain Circuits Underlying Narcolepsy

Narcolepsy is a sleep disorder manifesting symptoms such as excessive daytime sleepiness and often cataplexy, a sudden and involuntary loss of muscle activity during wakefulness. The underlying neuropathological basis of narcolepsy is the loss of orexin neurons from the lateral hypothalamus. To date numerous animal models of narcolepsy have been produced in the laboratory, being invaluable tools for delineating the brain circuits of narcolepsy. This review will examine the evidence regarding the function of the orexin system, and how loss of this wake-promoting system manifests in excessive daytime sleepiness. This review will also outline the brain circuits controlling cataplexy, focusing on the contribution of orexin signaling loss in narcolepsy. Although our understanding of the brain circuits of narcolepsy has made great progress in recent years, much remains to be understood.

Identification of a stress-sensitive anorexigenic neurocircuit from medial prefrontal cortex to lateral hypothalamus in humans and mice

Animal models that examine neural circuits controlling food intake often lack translational relevance. To address this limitation, we identified neural network dynamics related to homeostatic state and BMI in humans. This approach predicted a novel pathway projecting from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LH) in humans. We then dissected the mechanistic underpinnings of this human-relevant mPFC-LH circuit in mice. Chemogenetic or optogenetic activation of the mPFC-LH pathway in mice suppressed food intake and motivated sucrose-seeking. Fibre photometry demonstrated this pathway was active in response to acute stress or prior to novel environment or object exposure, suggesting a role in the predictive assessment of potential threat. Food consumption suppressed mPFC-LH neuronal activity, independent of metabolic state or palatability. Finally, inhibition of this circuit increased feeding and motivated behaviour under mild stress and chronic ablation caused weight gain. These studies identify the mPFC-LH as a novel stress-sensitive anorexigenic neural pathway involved in the cortical control of food intake and motivated reward-seeking.

Activity of the Lateral Hypothalamus during Genetically Determined Absence Seizures

(1) Background: Absence seizures (ASs) are sudden, transient lapses of consciousness associated with lack of voluntary movements and generalized 2.5–4 Hz spike-wave discharges (SWDs) in the EEG. In addition to the thalamocortical system, where these pathological oscillations are generated, multiple neuronal circuits have been involved in their modulation and associated comorbidities including the serotonergic system. Neuronal activity in one of the major synaptic input structures to the brainstem dorsal raphé nucleus (DRN), the lateral hypothalamus (LH), has not been characterized. (2) Methods: We used viral tract tracing and optogenetics combined with in vitro and in vivo electrophysiology to assess the involvement of the LH in absence epilepsy in a genetic rodent model. (3) Results: We found that a substantial fraction of LH neurons project to the DRN of which a minority is GABAergic. The LH to DRN projection can lead to monosynaptic iGluR mediated excitation in DRN 5-HT neurons. Neuronal activity in the LH is coupled to SWDs. (4) Conclusions: Our results indicate that a brain area involved in the regulation of autonomic functions and heavily innervating the RN is involved in ASs. The decreased activity of LH neurons during SWDs could lead to both a decreased excitation and disinhibition in the DRN. These results support a long-range subcortical regulation of serotonergic neuromodulation during ASs and further our understanding of the state-dependence of these seizures and some of their associated comorbidities.

Lateral hypothalamus involvement in control of stress response by bed nucleus of the stria terminalis endocannabinoid neurotransmission in male rats

The endocannabinoid neurotransmission acting via local CB1 receptor in the bed nucleus of the stria terminalis (BNST) has been implicated in behavioral and physiological responses to emotional stress. However, the neural network related to this control is poorly understood. In this sense, the lateral hypothalamus (LH) is involved in stress responses, and BNST GABAergic neurons densely innervate this hypothalamic nucleus. However, a role of BNST projections to the LH in physiological responses to stress is unknown. Therefore, using male rats, we investigated the role of LH GABAergic neurotransmission in the regulation of cardiovascular responses to stress by CB1 receptors within the BNST. We observed that microinjection of the selective CB1 receptor antagonist AM251 into the BNST decreased the number of Fos-immunoreactive cells within the LH of rats submitted to acute restraint stress. Treatment of the BNST with AM251 also enhanced restraint-evoked tachycardia. Nevertheless, arterial pressure increase and sympathetically-mediated cutaneous vasoconstriction to restraint was not affected by CB1 receptor antagonism within the BNST. The effect of AM251 in the BNST on restraint-evoked tachycardia was abolished in animals pretreated with the selective GABAA receptor antagonist SR95531 in the LH. These results indicate that regulation of cardiovascular responses to stress by CB1 receptors in the BNST is mediated by GABAergic neurotransmission in the LH. Present data also provide evidence of the BNST endocannabinoid neurotransmission as a mechanism involved in LH neuronal activation during stressful events.