Emerging many-to-one weighted mapping in hippocampus-amygdala network underlies memory formation.

Memories are crucial for our daily lives, yet the network-level organizing principle that governs neural representations of our experiences remains to be determined. Employing dual-site electrophysiology recording in freely behaving mice, we discovered that hippocampal dorsal CA1 (dCA1) and basolateral amygdala (BLA) utilize distinct coding strategies to represent novel experiences. A small assembly of BLA neurons rapidly emerged during memory acquisition and remained active during subsequent consolidation, whereas the majority of dCA1 neurons engaged in the same processes. Machine learning decoding revealed that dCA1 population spikes predicted the BLA assembly firing rate. This suggests that most dCA1 neurons concurrently index an episodic event by rapidly establishing weighted communications with a specific BLA assembly, a process we call "many-to-one weighted mapping." Furthermore, we demonstrated that closed-loop optoinhibition of BLA activity triggered by dCA1 ripples after new learning resulted in impaired memory. These findings highlight a new principle of hippocampus-amygdala communication underlying memory formation and provide new insights into how the brain creates and stores memories.

The two tales of hippocampal sharp-wave ripple content: The rigid and the plastic.

Sharp-wave ripples, prominently in the CA1 region of the hippocampus, are short oscillatory events accompanied by bursts of neural firing. Ripples and associated hippocampal place cell sequences communicate with cortical ensembles during slow-wave sleep, which has been shown to be critical for systems consolidation of episodic memories. This consolidation is not limited to a newly formed memory trace; instead, ripples appear to reactivate and consolidate memories spanning various experiences. Despite this broad spanning influence, ripples remain capable of producing precise memories. The underlying mechanisms that enable ripples to consolidate memories broadly and with specificity across experiences remain unknown. In this review, we discuss data that uncovers circuit-level processes that generate ripples and influence their characteristics during consolidation. Based on current knowledge, we propose that memory emerges from the integration of two parallel consolidation pathways in CA1: the rigid and plastic pathways. The rigid pathway generates ripples stochastically, providing a backbone upon which dynamic plastic pathway inputs carrying novel information are integrated.

Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation.

Although neurologic symptoms occur in two-thirds of lysosomal storage disorders (LSDs), for most we do not understand the mechanisms underlying brain dysfunction. A major unanswered question is if the pathogenic hallmark of LSDs, storage accumulation, induces functional defects directly or is a disease bystander. Also, for most LSDs we do not know the impact of loss of function in individual cell types. Understanding these critical questions are essential to therapy development. Here, we determine the impact of genetic rescue in distinct cell types on neural circuit dysfunction in CLN3 disease, the most common pediatric dementia and a paradigmatic neurodegenerative LSD. We restored Cln3 expression via AAV-mediated gene delivery and conditional genetic rescue in a CLN3 disease mouse model. Surprisingly, we found that low-level rescue of Cln3 expression in neurons alone normalized clinically relevant electrophysiologic markers of network dysfunction, despite the presence of substantial residual histopathology, in contrast to restoring expression in astrocytes. Thus, loss of CLN3 function in neurons, not storage accumulation, underlies neurologic dysfunction in CLN3 disease. This impliesies that storage clearance may be an inappropriate target for therapy development and an ineffectual biomarker.

Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder.

Accumulation of lysosomal storage material and late-stage neurodegeneration are hallmarks of lysosomal storage disorders (LSDs) affecting the brain. Yet, for most LSDs, including CLN3 disease, the most common form of childhood dementia, it is unclear what mechanisms drive neurologic symptoms. Do deficits arise from loss of function of the mutated protein or toxicity from storage accumulation? Here, using in vitro voltage-sensitive dye imaging and in vivo electrophysiology, we find progressive hippocampal dysfunction occurs before notable lysosomal storage and neuronal loss in 2 CLN3 disease mouse models. Pharmacologic reversal of lysosomal storage deposition in young mice does not rescue this circuit dysfunction. Additionally, we find that CLN3 disease mice lose an electrophysiologic marker of new memory encoding - hippocampal sharp-wave ripples. This discovery, which is also seen in Alzheimer's disease, suggests the possibility of a shared electrophysiologic signature of dementia. Overall, our data describe new insights into previously unknown network-level changes occurring in LSDs affecting the central nervous system and highlight the need for new therapeutic interventions targeting early circuit defects.