Silent memory engrams as the basis for retrograde amnesia

Recent studies identified neuronal ensembles and circuits that hold specific memory information (memory engrams). Memory engrams are retained under protein synthesis inhibition-induced retrograde amnesia. These engram cells can be activated by optogenetic stimulation for full-fledged recall, but not by stimulation using natural recall cues (thus, amnesia). We call this state of engrams “silent engrams” and the cells bearing them “silent engram cells.” The retention of memory information under amnesia suggests that the time-limited protein synthesis following learning is dispensable for memory storage, but may be necessary for effective memory retrieval processes. Here, we show that the full-fledged optogenetic recall persists at least 8 d after learning under protein synthesis inhibition-induced amnesia. This long-term retention of memory information correlates with equally persistent retention of functional engram cell-to-engram cell connectivity. Furthermore, inactivation of the connectivity of engram cell ensembles with its downstream counterparts, but not upstream ones, prevents optogenetic memory recall. Consistent with the previously reported lack of retention of augmented synaptic strength and reduced spine density in silent engram cells, optogenetic memory recall under amnesia is stimulation strength-dependent, with low-power stimulation eliciting only partial recall. Finally, the silent engram cells can be converted to active engram cells by overexpression of α-p-21–activated kinase 1, which increases spine density in engram cells. These results indicate that memory information is retained in a form of silent engram under protein synthesis inhibition-induced retrograde amnesia and support the hypothesis that memory is stored as the specific connectivity between engram cells.RIKEN Brain Science InstituteHoward Hughes Medical InstituteJPB Foundatio

Synaptic and cellular organization of layer 1 of the developing rat somatosensory cortex

Layer 1 of the neocortex is sparsely populated with neurons and heavily innervated by fibers from lower layers and proximal and distal brain regions. Understanding the potential functions of this layer requires a comprehensive understanding of its cellular and synaptic organization. We therefore performed a quantitative study of the microcircuitry of neocortical layer 1 (L1) in the somatosensory cortex in juvenile rats (P13-P16) using multi-neuron patch-clamp and 3D morphology reconstructions. Expert-based subjective classification of the morphologies of the recorded L1 neurons suggest 6 morphological classes: (1) the Neurogliaform cells with dense axonal arborizations (NGC-DA) and with sparse arborizations (NGC-SA), (2) the Horizontal Axon Cell (HAC), (3) those with descending axonal collaterals (DAC), (4) the large axon cell (LAC), and (5) the small axon cell (SAC). Objective, supervised and unsupervised cluster analyses confirmed DAC, HAC, LAC and NGC as distinct morphological classes. The neurons were also classified into 5 electrophysiological types based on the Petilla convention; classical non-adapting (cNAC), burst non-adapting (bNAC), classical adapting (cAC), classical stuttering (cSTUT), and classical irregular spiking (cIR). The most common electrophysiological type of neuron was the cNAC type (40%) and the most common morpho-electrical type was the NGC-DA cNAC. Paired patch-clamp recordings revealed that the neurons were connected via GABAergic inhibitory synaptic connections with a 7.9% connection probability and via gap junctions with a 5.2% connection probability. Most synaptic connections were mediated by both GABA(A) and GABA(B) receptors (62.6%). A smaller fraction of synaptic connections were mediated exclusively by GABAA (15.4%) or GABAB (21.8%) receptors. Morphological 3D reconstruction of synaptic connected pairs of L1 neurons revealed multi-synapse connections with an average of 9 putative synapses per connection. These putative synapses were widely distributed with 39% on somata and 61% on dendrites. We also discuss the functional implications of this L1 cellular and synaptic organization in neocortical information processing

Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors

Basolateral amygdala (BLA) principal cells are capable of driving and antagonizing behaviors of opposing valence. BLA neurons project to the central amygdala (CeA), which also participates in negative and positive behaviors. However, the CeA has primarily been studied as the site for negative behaviors, and the causal role for CeA circuits underlying appetitive behaviors is poorly understood. Here, we identify several genetically distinct populations of CeA neurons that mediate appetitive behaviors and dissect the BLA-to-CeA circuit for appetitive behaviors. Protein phosphatase 1 regulatory subunit 1B⁺ BLA pyramidal neurons to dopamine receptor 1⁺ CeA neurons define a pathway for promoting appetitive behaviors, while R-spondin 2⁺ BLA pyramidal neurons to dopamine receptor 2⁺ CeA neurons define a pathway for suppressing appetitive behaviors. These data reveal genetically defined neural circuits in the amygdala that promote and suppress appetitive behaviors analogous to the direct and indirect pathways of the basal ganglia. Keywords: central amygdala; basolateral amygdala; direct and indirect pathways; appetitive; reward; fear; amygdala circuit; feeding; drinking; freezingNational Institutes of Health (U.S.) (Grant T32GM007287

Reconstruction and simulation of neocortical microcircuitry

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm3 containing ∼31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ∼8 million connections with ∼37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies

Engram Cell Excitability State Determines the Efficacy of Memory Retrieval

Animals need to optimize the efficacy of memory retrieval to adapt to environmental circumstances for survival. The recent development of memory engram labeling technology allows a precise investigation of the processes associated with the recall of a specific memory. Here, we show that engram cell excitability is transiently increased following memory reactivation. This short-term increase of engram excitability enhances the subsequent retrieval of specific memory content in response to cues and is manifest in the animal's ability to recognize contexts more precisely and more effectively. These results reveal a hitherto unknown transient enhancement of context recognition based on the plasticity of engram cell excitability. They also suggest that recall of a contextual memory is influenced by previous but recent activation of the same engram. The state of excitability of engram cells mediates differential behavioral outcomes upon memory retrieval and may be crucial for survival by promoting adaptive behavior

Cingulate-motor circuits update rule representations for sequential choice decisions

AbstractAnterior cingulate cortex mediates the flexible updating of an animal’s choice responses upon rule changes in the environment. However, how anterior cingulate cortex entrains motor cortex to reorganize rule representations and generate required motor outputs remains unclear. Here, we demonstrate that chemogenetic silencing of the terminal projections of cingulate cortical neurons in secondary motor cortex in the rat disrupts choice performance in trials immediately following rule switches, suggesting that these inputs are necessary to update rule representations for choice decisions stored in the motor cortex. Indeed, the silencing of cingulate cortex decreases rule selectivity of secondary motor cortical neurons. Furthermore, optogenetic silencing of cingulate cortical neurons that is temporally targeted to error trials immediately after rule switches exacerbates errors in the following trials. These results suggest that cingulate cortex monitors behavioral errors and updates rule representations in motor cortex, revealing a critical role for cingulate-motor circuits in adaptive choice behaviors.</jats:p

Heterophilic Type II Cadherins Are Required for High-Magnitude Synaptic Potentiation in the Hippocampus.

Hippocampal CA3 neurons form synapses with CA1 neurons in two layers, stratum oriens (SO) and stratum radiatum (SR). Each layer develops unique synaptic properties but molecular mechanisms that mediate these differences are unknown. Here, we show that SO synapses normally have significantly more mushroom spines and higher-magnitude long-term potentiation (LTP) than SR synapses. Further, we discovered that these differences require the Type II classic cadherins, cadherins-6, -9, and&nbsp;-10. Though cadherins typically function via trans-cellular homophilic interactions, our results suggest presynaptic cadherin-9 binds postsynaptic cadherins-6 and -10 to regulate mushroom spine density and high-magnitude LTP in the SO layer. Loss of these cadherins has no effect on the lower-magnitude LTP typically observed in the SR layer, demonstrating that cadherins-6, -9, and -10 are gatekeepers for high-magnitude LTP. Thus, Type II cadherins may uniquely contribute to the specificity and strength of synaptic changes associated with learning and memory

Association between Multiple Myeloma and Ulcerative Colitis: A Cross-Sectional Analysis

Background and Aims: Multiple myeloma (MM) is a plasma cell dyscrasia that is common among patients with autoimmune diseases. However, the association between ulcerative colitis (UC) and multiple myeloma (MM) is yet to be established. We aimed to evaluate the prevalence of MM among patients with UC in the United States. Methods: This cross-sectional cohort analysis used the National Inpatient Sample from 2015–2018 to assess the overall MM prevalence among patients with and without UC, and within specific demographic subgroups. Prevalences were compared using a logistic regression model controlling for sex and age. Results: The crude prevalence of MM among patients with UC (n = 1750) compared with patients without UC (n = 366,265) was 0.44% vs. 0.37%, respectively. Patients with UC had increased overall odds of having MM (odds ratio (OR), 1.26). Males with UC had higher prevalence of MM (53.7% vs. 46.3%, respectively) than females. Patients with UC and MM were more likely to be African American than White (15.6% vs. 9.2%, respectively). Patients with UC age >64 had a higher prevalence of MM than those aged below 65 (70.9% vs. 29.1%, respectively). Patients with UC who were obese (BMI > 30) had a higher prevalence of MM than those who were non-obese (12.6% vs. 8.3%). Conclusions: Overall, UC appears to be associated with MM. This association can be particularly observed in specific demographic groups, such as obese, African American males, or patients >64 years of age. Thus, a high degree of clinical suspicion for MM is warranted, even with minimal symptomatology, in patients with UC, in particular among elder, obese, and African American males