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Regulated fear and extinction memory is essential for balanced behavioral response. Limbic brain regions are susceptible to hypobaric hypoxia (HH) and are putative target for fear extinction deficit and dysregulation. The present study aimed to examine the effect of HH and Ginkgo biloba extract (GBE) on fear and extinction memory with the underlying mechanism. Adult male Sprague-Dawley rats were evaluated for fear extinction and anxious behavior following GBE administration during HH exposure. Blood and tissue (PFC, hippocampus and amygdala) samples were collected for biochemical, morphological and molecular studies. Results revealed deficit in contextual and cued fear extinction following 3 days of HH exposure. Increased corticosterone, glutamate with decreased GABA level was found with marked pyknosis, decrease in apical dendritic length and number of functional spines. Decline in mRNA expression level of synaptic plasticity genes and immunoreactivity of BDNF, synaptophysin, PSD95, spinophilin was observed following HH exposure. GBE administration during HH exposure improved fear and extinction memory along with decline in anxious behavior. It restored corticosterone, glutamate and GABA levels with an increase in apical dendritic length and number of functional spines with a reduction in pyknosis. It also improved mRNA expression level and immunoreactivity of neurotrophic and synaptic proteins. The present study is the first which demonstrates fear extinction deficit and anxious behavior following HH exposure. GBE administration ameliorated fear and extinction memory dysregulation by restoration of neurotransmitter levels, neuronal pyknosis and synaptic connections along with improved neurotrophic and synaptic protein expressions., Competing Interests: Declaration of Competing Interest There are no competing interests, financial or otherwise., (Copyright © 2020. Published by Elsevier B.V.)

Hypobaric hypoxia (HH) is an environmental stress encountered at high altitude. It has been shown that HH resulted in spine atrophy and working memory deficits. Kalirin-7, a postsynaptic density protein, plays an important and key role in regulating spine dynamics and its plasticity. Spine atrophy is implicated in HH induced memory deficits but role of Kalirin-7 in this phenomenon is not studied. Present study is therefore designed to investigate the effect of chronic HH exposure on Kalirin-7 expression in hippocampus and its role in spatial working memory deficits. Adult rats (n = 12, 3 months old) were exposed to a simulated altitude of 25,000 feet for 7 days. Following HH exposure, spatial working memory was assessed with Radial arm maze and T maze. Hippocampal expression of Kalrin-7 was estimated at mRNA and protein levels. Results of behavioural experiments showed that HH causes significant decrease in the spatial working memory. There was a significant reduction in the protein expression of Kalirin-7 in the hippocampus of hypoxia exposed rats (43.89 ± 7.43) as compared to the control (69.54 ± 10.99). The mRNA expression of Kalrin-7 also exhibits significant reduction (0.59 ± 0.05) in the exposed group as compared to the control (0.98 ± 0.07). Immunohistochemistry showed that Kalirin-7 is decreased significantly in CA1, CA3 and DG regions of the hippocampus. Moreover, memory deficits are significantly correlated with decreased immunoreactivity of the hippocampal Kalirin-7. In conclusion, it can be said therefore, that change in Kalirin-7 expression in the hippocampus is associated with HH induced working memory deficit., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Fear memory is essential for survival, and its dysregulation leads to disorders. High altitude hypobaric hypoxia (HH) is known to induce cognitive decline. However, its effect on fear memory is still an enigma. We aimed to investigate the temporal effect of HH on fear conditioning and the underlying mechanism. Adult male Sprague-Dawley rats were trained for fear conditioning and exposed to simulated HH equivalent to 25,000 ft for different durations (1, 3, 7, 14 and 21 days). Subsequently, rats were tested for cued and contextual fear conditioning. Neuronal morphology, apoptosis and DNA fragmentation were studied in the medial prefrontal cortex (mPFC), hippocampus and basolateral amygdala (BLA). We observed significant deficit in cued and contextual fear acquisition (at 1, 3 and 7 days) and consolidation (cued at 1 and 3 days and contextual fear at 1, 3 and 7 days) under HH. HH exposure with retraining showed the earlier restoration of contextual fear memory. Further, we found a gradual increase in the number of pyknotic and apoptotic neurons together with the increase in DNA fragmentation in mPFC, hippocampus, and BLA up to 7 days of HH exposure. The present study concludes that HH exposure equivalent to 25,000 ft induced cued and contextual fear memory deficit (acquisition and consolidation) which is found to be correlated with the neurodegenerative changes in the limbic brain regions., (Copyright © 2018. Published by Elsevier B.V.)