The Role Of Dorsal CA1 Interneuron Subtypes In Stress-Induced Memory Deficits

Exposure to severely stressful experiences disrupts the activity of neuronal circuits and impairs hippocampus-dependent cognition.GABAergic intemeurons coordinate neuronal network activity,but their involvement in acute stress-evoked memory loss remains unclear.Here,we provide evidence that intemeurons in area CA1 of the dorsal hippocampus modulate acute stress-induced memory deficits.At first,forced swim(5 min)and restraint stress(30 min)were applied to investigate the effects of acute stress on spatial memory and the activity of dorsal CAI interneurons in mice.To micmic the effects of acute stress,we then used a chemogenetic approach to specifically activate dorsal CA1 intemeurons in order to study its effects on anxiety and memory by using a series of behavioral tests including open field,light-dark box,elevated plus maze,Y maze,spatial object recognition and novel object recognition tests.We also explored the mechanisms underlying behavioral changes caused by activating dorsal CA1 intemeurons.At last,we chemogenetically inhibited dorsal CA1 intemeuron activity during stress exposure to explore whether it could rescue acute stress-induced spatial memory loss.The results showed that in adult male C57BL/6N mice,both acute forced swim stress and restraint stress impaired spatial memory and increased the density of activated intemeurons in the dorsal CAI.Selective activation of dorsal CA1 inteneurons disrupted long-term spatial memory specificly.Moreover,activation of dorsal CA1 intemeurons suppressed the activity of adjacent pyramidal neurons,while the density of excitatory and inhibitory synapses remained unchanged.These findings suggest that acute stress may overactivate intemeurons in the dorsal CA1,which reduces the activity of pyramidal neurons and in turn disrupts long-term memory.However,inhibition of dorsal CA1 intemeurons failed to rescue or ameliorate acute stress-induced spatial memory impairments,Dorsal CA1 intemeurons are classified into diverse subtypes according to molecular,structural and electrophysiological properties.Each subtype may play distinct roles in acute stress-induced spatial memory deficits.Based on the findings mentioned above,we further studied the role of CRH interneurons in acute stress-induced memory loss.At first,forced swim(5 min)and restraint stress(30 min)were applied to investigate the effects of acute stress on the activity of dorsal CA1 CRH interneurons.We then used chemogenetics to selectively activate dorsal CA1 CRH intemeurons to examine its effects on memory and explore the underlying mechanisms.The results showed that in adult male CRH-GFP mice,acute forced swim stress significantly increased the number of activited CRH intemeurons in the dorsal CAI.Chemogenetic activation of dorsal CA1 CRH intemeurons at different memory stages disrupted memory acquisition,consolidation and retrieval in the spatial object recognition task,which was attributed to the over-release of the CRH peptide.In conclusion,our results suggest that dorsal CA1 intemeurons and CRH intemeurons modulate acute stress-induced memory deficits.The findings may provide new mechanistic insights into acute stress-related cognition impairments.Calbindin modulates intracellular Ca2+ dynamics and synaptic plasticity.Reduction of hippocampal calbindin levels has been implicated in stress-related cognitive disorders,but it remains unclear how calbindin-expressing interneurons in hippocampal CA1 contribute to acute stress-induced memory loss.Here,we provide evidence that calbindinexpressing interneurons in the dorsal CA1 modulate resistance to acute stress-induced memory deficits.We injected a Cre-dependent calbindin knock-down virus into the dorsal CA1 region of adult male GAD65-Cre mice to selectively knockdown calbindin in interneurons,and used a battery of behavioral tests including novelty suppression of feeding,open field,light-dark box,elevated plus maze,delayed non-match to sample,and spatial object recognition tests to examine its effects on anxiety-related behavior and hippocampus-dependent memory both under basal conditions and after acute stress.The results showed that short-term spatial working memory was only subtly impaired in mice with calbindin knockdown in dorsal CA1 interneurons.Moreover,calbindin knockdown in CA1 interneurons preserved long-term spatial memory both under basal conditions and following a forced swim stress,indicating increased resilience to the negative stress effects on memory.Calbindin knockdown in dorsal CA1 interneurons did not affect anxiety-related behavior.In addition,we found that the synaptic cell adhesion molecule nectin-3 colocalized with calbindin in dorsal CA1 interneurons,indicating that nectin-3may interact with calbindin to modulate the resistance to acute stress-induced memory deficits,which needs further investigations.In summary,our study reveals that calbindinexpressing interneurons in the dorsal CA1 modulate the resistance to acute stress-induced memory deficits.These findings may help understand the cellular mechanisms of acute stress-induced cognitive deficits.