Background
Exposure to juvenile stress was found to have long-term effects on plasticity and the quality of associative memory in adulthood, but the underlying mechanisms are still poorly understood.
Methods
3-4-week-old male Wistar rats were subjected to a three-day juvenile stress paradigm. Their electrophysiological correlates of memory using the adult hippocampal slice were inspected to detect alterations in long-term potentiation and synaptic tagging and capture model of associativity. These cellular alterations were tied in with the behavioural outcome by subjecting the rats to a step-down inhibitory avoidance paradigm to measure strength in their memory. Given the role of epigenetic response in altering plasticity as a repercussion of juvenile stress, we set forth to chart out the possible epigenetic marker and its regulation in the long-term memory mechanisms using qRT-PCR.
Results
We demonstrate that even long after the elimination of actual stressors, an inhibitory metaplastic state is evident, which promotes synaptic competition over synaptic co-operation and decline in latency of associative memory in the behavioural paradigm despite the exposure to novelty. Mechanistically, juvenile stress led to a heightened expression of the epigenetic marker G9a/GLP complex which is thus far ascribed to transcriptional silencing and goal directed behaviour.
Conclusions
The blockade of the G9a/GLP complex was found to alleviate deficits in long-term plasticity and associative memory during the adulthood of animals that were exposed to juvenile stress. Our data provides insights on the long-term effects of juvenile stress that involve epigenetic mechanisms, which directly impact long-term plasticity, synaptic tagging and capture and associative memory.
This chapter discusses the role of protein synthesis in the maintenance of long-term potentiation (LTP) and its associative properties, synaptic tagging and capture, which are cellular correlates of long-term memory. Starting from a brief overview of the early and late phases of LTP, the chapter discusses various existing models for synaptic activity-induced protein synthesis and its roles in late-LTP. The synaptic tagging and capture and cross-tagging theories are given emphasis, along with the elucidation of local dendritic protein synthesis and its significance in the maintenance of LTP. Inverse synaptic tagging, synaptic competition for plasticity-related proteins, and metaplasticity are also covered. The importance of the balance between proteasomal degradation and synthesis of plasticity-related proteins in persistent potentiation is briefly discussed. This chapter touches upon the physiological implications of epigenetic regulation in the control of neuronal functions and the molecular mechanisms within the neurons that translate epigenetic changes into long-lasting responses.
The hippocampal CA2 region has received greater attention in recent years due to its fundamental role in social memory and hippocampus-dependent memory processing.Unlike entorhinal cortical inputs, the Schaffer collateral inputs to CA2 do not support activity-dependent long-term potentiation (LTP), which serves as the basis for longterm memories. This LTP-resistant zone also expresses genes that restrict plasticity.With the aim of exploring social interaction and sociability in rats that were subjected to juvenile stress, we addressed questions about how the neural circuitry is altered and its effects on social behavior. Although there was induction of LTP in both Schaffer collateral and entorhinal cortical pathways in juvenile-stressed rats, LTP declined in both pathways after 2-3 h. Moreover, exogenous bath application of substance P, a neuropeptide that resulted in slow onset long-lasting potentiation in control animals while it failed to induce LTP in juvenile-stressed rats. Our study reveals that juvenilestressed rats show behavioral and cellular abnormalities with a long-lasting impact in adulthood.
Encoding and predicting aversive events are critical functions of circuits that support survival and emotional well-being. Maladaptive circuit changes in emotional valence processing can underlie the pathophysiology of affective disorders. The lateral habenula (LHb) has been linked to aversion and mood regulation through modulation of the dopamine and serotonin systems. We have defined the identity and function of glutamatergic (Vglut2) control of the LHb, comparing the role of inputs originating in the globus pallidus internal segment (GPi), and lateral hypothalamic area (LHA), respectively. We found that LHb-projecting LHA neurons, and not the proposed GABA/glutamate co-releasing GPi neurons, are responsible for encoding negative value. Monosynaptic rabies tracing of the presynaptic organization revealed a predominantly limbic input onto LHA Vglut2 neurons, while sensorimotor inputs were more prominent onto GABA/glutamate co-releasing GPi neurons. We further recorded the activity of LHA Vglut2 neurons, by imaging calcium dynamics in response to appetitive versus aversive events in conditioning paradigms. LHA Vglut2 neurons formed activity clusters representing distinct reward or aversion signals, including a population that responded to mild foot shocks and predicted aversive events. We found that the LHb-projecting LHA Vglut2 neurons encode negative valence and rapidly develop a prediction signal for negative events. These findings establish the glutamatergic LHA-LHb circuit as a critical node in value processing.
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