Similar to elderly humans, aged outbred Long Evans rats exhibit individual differences in memory abilities, including a subset of aged rats that maintain memory function on par with young adults. Such individuals provide a basis for investigating mechanisms of resilience to age-related decline. The present study examined hippocampal gene expression in young adults and aged rats with preserved memory function under behavioral task conditions well-established for assessing information processing central to the formation of episodic memory. While behavioral measures and hippocampal gene induction associated with neural activity and synaptic plasticity were similar across age groups, a marker for inhibitory interneuron function in the hippocampal formation was distinctively increased only in aged rats but not in young adults. Because heightened hippocampal neural activity is associated with age-related memory impairment across species, including rats, monkeys and humans, this finding may represent an adaptive homeostatic adjustment necessary to maintain neural plasticity and memory function in aging.
The formation and extinction of fear memories represent two forms of learning that each engage the hippocampus and amygdala. How cell populations in these areas contribute to fear relapse, however, remains unclear. Here, we demonstrate that, in male mice, cells active during fear conditioning in the dentate gyrus of hippocampus exhibit decreased activity during extinction and are re-engaged after contextual fear relapse. In vivo calcium imaging reveals that relapse drives population dynamics in the basolateral amygdala to revert to a network state similar to the state present during fear conditioning. Finally, we find that optogenetic inactivation of neuronal ensembles active during fear conditioning in either the hippocampus or amygdala is sufficient to disrupt fear expression after relapse. These results suggest that fear relapse triggers a partial re-emergence of the original fear memory representation, providing new insight into the neural substrates of fear relapse. IntroductionThe biological capacity to produce adaptive behavioral responses in actively changing environments is critical to an animal's survival. Contextual fear conditioning (CFC) is a form of learning whereby an animal learns to associate a conditioned stimulus (i.e. a context) with an unconditioned aversive stimulus (e.g. foot shocks) to produce a conditioned response to the conditioned stimulus (e.g. freezing). Conditioned responses can be mitigated through extinction learning via repeated exposure to the conditioned context in the absence of the foot shock. However, while extinction learning can be effective at attenuating fear, animals are susceptible to fear relapse under several conditions, including exposure to stressors, the passage of time, and re-exposure to the unconditioned stimulus (
Similar to elderly humans, aged Long–Evans rats exhibit individual differences in performance on tasks that critically depend on the medial temporal lobe memory system. Although reduced memory performance is common, close to half of aged rats in this outbred rodent population perform within the range of young subjects, exhibiting a stable behavioral phenotype that may signal a resilience to memory decline. Increasing evidence from research on aging in the Long–Evans study population supports the existence of adaptive neural change rather than avoidance of detrimental effects of aging on the brain, indicating a malleability of brain function over the life span that may preserve optimal function. Augmenting prior work that centered on hippocampal function, the current study extends investigation to cortical regions functionally interconnected with the hippocampal formation, including medial temporal lobe cortices and posterior components of the default mode network. In response to an environmental manipulation that creates a mismatch in the expected cue orientation, aged rats with preserved memory show greater activation across an extended network of cortical regions as measured by immediate early gene expression. In contrast, young subjects, behaviorally similar to the aged rats in this study, show a more limited cortical response. This distinctive cortical recruitment in aged unimpaired rats, set against a background of comparable activation across hippocampal subregions, may represent adaptive cortical recruitment consistent with evidence in human studies of neurocognitive aging.
10The hippocampus processes both spatial-temporal information and emotionally salient 11 experiences. To test the functional properties of discrete sets of cells in the dorsal dentate gyrus 12 (dDG), we examined whether chronic optogenetic reactivation of these ensembles was 13 sufficient to modulate social behaviors in mice. We found that chronic reactivation of dDG cells 14 in male mice was sufficient to enhance social behaviors in a female exposure task when 15 compared to pre-stimulation levels. However, chronic reactivation of these cells was not 16 sufficient to modulate group differences in a separate subset of social behaviors, and multi-17 region analysis of neural activity did not yield detectable differences in immediate-early gene 18 expression or neurogenesis, suggesting a dissociation between our chronic stimulation-induced 19 behavioral effects and underlying neural responses. Together, our results demonstrate that 20 chronic optogenetic stimulation of cells processing valent experiences enduringly and 21 unidirectionally modulates social interactions between male and female mice. 22 23 Chen et al., 2019). To test whether or not our chronic stimulation strategy generalizes to other 35 behaviors, here we examined whether chronic optogenetic reactivation of ensembles in the dDG 36 which are active during putative positive or negative experiences is sufficient to alter social 37 behaviors as well as the activity of multiple brain regions. 38 39 2. Methods 40 Subjects 41Wild-type C57BL/6N male mice (40-41 days; Charles River Laboratories) were housed with 42 littermates in groups of 2-5 mice per cage. Mice were acclimated to the animal facility for 72 43 hours upon delivery before experimental procedures began and kept on a 12:12-hour light cycle 44 (lights on at 7:00). Food and water were available ad libitum. Animals were put on a diet 45 containing 40 mg/kg doxycycline (dox) after the acclimation period and 24-48 hours before 46 receiving surgery between 6-7 weeks of age. Following surgery, mice were group-housed with 47
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