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Cerebellar modulation of memory encoding in the periaqueductal grey and fear behaviour.

ABSTRACT: The pivotal role of the periaqueductal grey (PAG) in fear learning is reinforced by the identification of neurons in male rat ventrolateral PAG (vlPAG) that encode fear memory through signalling the onset and offset of an auditory-conditioned stimulus during presentation of the unreinforced conditioned tone (CS+) during retrieval. Some units only display CS+ onset or offset responses, and the two signals differ in extinction sensitivity, suggesting that they are independent of each other. In addition, understanding cerebellar contributions to survival circuits is advanced by the discovery that (i) reversible inactivation of the medial cerebellar nucleus (MCN) during fear consolidation leads in subsequent retrieval to (a) disruption of the temporal precision of vlPAG offset, but not onset responses to CS+, and (b) an increase in duration of freezing behaviour. And (ii) chemogenetic manipulation of the MCN-vlPAG projection during fear acquisition (a) reduces the occurrence of fear-related ultrasonic vocalisations, and (b) during subsequent retrieval, slows the extinction rate of fear-related freezing. These findings show that the cerebellum is part of the survival network that regulates fear memory processes at multiple timescales and in multiple ways, raising the possibility that dysfunctional interactions in the cerebellar-survival network may underlie fear-related disorders and comorbidities.

SUBMITTER: Lawrenson C

PROVIDER: S-EPMC8923669 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The ventromedial hypothalamus is a central node of the mammalian predator defense network. Stimulation of this structure in rodents and primates elicits abrupt defensive responses, including flight, freezing, sympathetic activation, and panic, while inhibition reduces defensive responses to predators. The major efferent target of the ventromedial hypothalamus is the dorsal periaqueductal gray (dPAG), and stimulation of this structure also elicits flight, freezing, and sympathetic activation. However, reversible inhibition experiments suggest that the ventromedial hypothalamus and periaqueductal gray play distinct roles in the control of defensive behavior, with the former proposed to encode an internal state necessary for the motivation of defensive responses, while the latter serves as a motor pattern initiator. Here, we used electrophysiological recordings of single units in behaving male mice exposed to a rat to investigate the encoding of predator fear in the dorsomedial division of the ventromedial hypothalamus (VMHdm) and the dPAG. Distinct correlates of threat intensity and motor responses were found in both structures, suggesting a distributed encoding of sensory and motor features in the medial hypothalamic-brainstem instinctive network.SIGNIFICANCE STATEMENT Although behavioral responses to predatory threat are essential for survival, the underlying neuronal circuits remain undefined. Using single unit in vivo electrophysiological recordings in mice, we have identified neuronal populations in the medial hypothalamus and brainstem that encode defensive responses to a rat predator. We found that both structures encode both sensory as well as motor aspects of the behavior although with different kinetics. Our findings provide a framework for understanding how innate sensory cues are processed to elicit adaptive behavioral responses to threat and will help to identify targets for the pharmacological modulation of related pathologic behaviors.

Project description:The existence of "sex phenotype" in migraine is a long-standing scientific question. Fluctuations of female sex hormones contribute to migraine attacks, and women also have enhanced brain activity during emotional processing and their functional brain networks seem to be more vulnerable to migraine-induced disruption compared to men. Periaqueductal grey matter (PAG) is a core region of pain processing and modulation networks with possible sex-related implications in migraine. In our study, sex differences of PAG functional resting-state connectivity were investigated in the interictal state in 32 episodic migraines without aura patients (16 women and 16 men). A significant main effect of sex was detected in PAG connectivity with postcentral, precentral, and inferior parietal gyri, and further differences were found between right PAG and visual areas (superior occipital gyrus, calcarine, and cuneus), supplementary motor area, and mid-cingulum connectivity. In all cases, PAG functional connectivity was stronger in female migraineurs compared to males. However, higher average pain intensity of migraine attacks correlated with stronger connectivity of PAG and middle temporal, superior occipital, and parietal gyri in male migraineurs compared to females. Migraine-related disability is also associated with PAG connectivity but without sex differences. Our results indicate that sex differences in PAG connectivity with brain regions involved in sensory and emotional aspects of pain might contribute to the "sex-phenotype" in migraine. The stronger functional connectivity between PAG and pain processing areas may be a sign of increased excitability of pain pathways even in resting-state in females compared to male migraineurs, which could contribute to female vulnerability for migraine. However, pain intensity experienced by male migraineurs correlated with increased connectivity between PAG and regions involved in the subjective experience of pain and pain-related unpleasantness. The demonstrated sex differences of PAG functional connectivity may support the notion that the female and male brain is differently affected by migraine.

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Cerebellar modulation of memory encoding in the periaqueductal grey and fear behaviour.

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