Organizational principles of amygdalar input-output neuronal circuits.

The amygdala, one of the most studied brain structures, integrates brain-wide heterogeneous inputs and governs multidimensional outputs to control diverse behaviors central to survival, yet how amygdalar input-output neuronal circuits are organized remains unclear. Using a simplified cell-type- and projection-specific retrograde transsynaptic tracing technique, we scrutinized brain-wide afferent inputs of four major output neuronal groups in the amygdalar basolateral complex (BLA) that project to the bed nucleus of the stria terminals (BNST), ventral hippocampus (vHPC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), respectively. Brain-wide input-output quantitative analysis unveils that BLA efferent neurons receive a diverse array of afferents with varied input weights and predominant contextual representation. Notably, the afferents received by BNST-, vHPC-, mPFC- and NAc-projecting BLA neurons exhibit virtually identical origins and input weights. These results indicate that the organization of amygdalar BLA input-output neuronal circuits follows the input-dependent and output-independent principles, ideal for integrating brain-wide diverse afferent stimuli to control parallel efferent actions. The data provide the objective basis for improving the virtual reality exposure therapy for anxiety disorders and validate the simplified cell-type- and projection-specific retrograde transsynaptic tracing method.

Mechanism of seizure-induced retrograde amnesia.

Seizures cause retrograde amnesia, but underlying mechanisms are poorly understood. We tested whether seizure activated neuronal circuits overlap with spatial memory engram and whether seizures saturate LTP in engram cells. A seizure caused retrograde amnesia for spatial memory task. Spatial learning and a seizure caused cFos expression and synaptic plasticity overlapping set of neurons in the CA1 of the hippocampus. Recordings from learning-labeled CA1 pyramidal neurons showed potentiated synapses. Seizure-tagged neurons were also more excitable with larger rectifying excitatory postsynaptic currents than surrounding unlabeled neurons. These neurons had enlarged dendritic spines and saturated LTP. A seizure immediately after learning, reset the memory engram. Seizures cause retrograde amnesia through shared ensembles and mechanisms.

Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology.

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase implicated in synaptic plasticity, behavior, and cognition, yet its synaptic function remains poorly understood. Here, we report that physiological Cdk5 signaling in rat hippocampal CA1 neurons regulates homeostatic synaptic transmission using an unexpectedly rapid mechanism that is different from all known slow homeostatic regulators, such as beta amyloid (Aß) and activity-regulated cytoskeleton-associated protein (Arc, aka Arg3.1). Interestingly, overproduction of the potent Cdk5 activator p25 reduces synapse density, and dynamically regulates synaptic size by suppressing or enhancing Aß/Arc production. Moreover, chronic overproduction of p25, seen in Alzheimer's patients, induces initially concurrent reduction in synapse density and increase in synaptic size characteristic of the early Alzheimer-like pathology, and later persistent synapse elimination in intact brains. These results identify Cdk5 as the regulator of a novel rapid form of homeostasis at central synapses and p25 as the first molecule capable of initiating the early Alzheimer's synaptic pathology.

Canonical Organization of Layer 1 Neuron-Led Cortical Inhibitory and Disinhibitory Interneuronal Circuits.

Interneurons play a key role in cortical function and dysfunction, yet organization of cortical interneuronal circuitry remains poorly understood. Cortical Layer 1 (L1) contains 2 general GABAergic interneuron groups, namely single bouquet cells (SBCs) and elongated neurogliaform cells (ENGCs). SBCs predominantly make unidirectional inhibitory connections (SBC→) with L2/3 interneurons, whereas ENGCs frequently form reciprocal inhibitory and electric connections (ENGC↔) with L2/3 interneurons. Here, we describe a systematic investigation of the pyramidal neuron targets of L1 neuron-led interneuronal circuits in the rat barrel cortex with simultaneous octuple whole-cell recordings and report a simple organizational scheme of the interneuronal circuits. Both SBCs→ and ENGC ↔ L2/3 interneuronal circuits connect to L2/3 and L5, but not L6, pyramidal neurons. SBC → L2/3 interneuronal circuits primarily inhibit the entire dendritic-somato-axonal axis of a few L2/3 and L5 pyramidal neurons located within the same column. In contrast, ENGC ↔ L2/3 interneuronal circuits generally inhibit the distal apical dendrite of many L2/3 and L5 pyramidal neurons across multiple columns. Finally, L1 interneuron-led circuits target distinct subcellular compartments of L2/3 and L5 pyramidal neurons in a L2/3 interneuron type-dependent manner. These results suggest that L1 neurons form canonical interneuronal circuits to control information processes in both supra- and infragranular cortical layers.