Optogenetic stimulation of a hippocampal engram activates fear memory recall

A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification3 and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.RIKEN Brain Science InstituteNational Institutes of Health (U.S.) (Grant R01-MH078821)National Institutes of Health (U.S.) (Grant P50-MH58880

Reward prediction error signals by reticular formation neurons

As a key part of the brain’s reward system, midbrain dopamine neurons are thought to generate signals that reflect errors in the prediction of reward. However, recent evidence suggests that “upstream” brain areas may make important contributions to the generation of prediction error signals. To address this issue, we recorded neural activity in midbrain reticular formation (MRNm) while rats performed a spatial working memory task. A large proportion of these neurons displayed positive and negative reward prediction error-related activity that was strikingly similar to that observed in dopamine neurons. Therefore, MRNm may be a source of reward prediction error signals

T‐type calcium channels as therapeutic targets in essential tremor and Parkinson's disease

Abstract Neuronal action potential firing patterns are key components of healthy brain function. Importantly, restoring dysregulated neuronal firing patterns has the potential to be a promising strategy in the development of novel therapeutics for disorders of the central nervous system. Here, we review the pathophysiology of essential tremor and Parkinson's disease, the two most common movement disorders, with a focus on mechanisms underlying the genesis of abnormal firing patterns in the implicated neural circuits. Aberrant burst firing of neurons in the cerebello‐thalamo‐cortical and basal ganglia‐thalamo‐cortical circuits contribute to the clinical symptoms of essential tremor and Parkinson's disease, respectively, and T‐type calcium channels play a key role in regulating this activity in both the disorders. Accordingly, modulating T‐type calcium channel activity has received attention as a potentially promising therapeutic approach to normalize abnormal burst firing in these diseases. In this review, we explore the evidence supporting the theory that T‐type calcium channel blockers can ameliorate the pathophysiologic mechanisms underlying essential tremor and Parkinson's disease, furthering the case for clinical investigation of these compounds. We conclude with key considerations for future investigational efforts, providing a critical framework for the development of much needed agents capable of targeting the dysfunctional circuitry underlying movement disorders such as essential tremor, Parkinson's disease, and beyond