RESUMO
One of the most fascinating aspects of the brain is its ability to acquire new information from experience and retain it over time as memory. The search for physical correlates of memory, the memory engram, has been a longstanding priority in modern neurobiology. Advanced genetic approaches have led to the localization of engram cells in a few brain regions, including the hippocampus and cortex. Additionally, engram cells exhibit learning-induced, persistent modifications and have at least two states, active and silent. However, it has been hypothesized that engrams for a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Recent tissue-clearing techniques have permitted high-throughput analyses of intact brain samples, which have been used to obtain a map of the engram complex for a contextual fear memory. Careful examination of these engram complex maps has revealed a potentially underappreciated contribution of subcortical regions, specifically thalamic nuclei, to memory function. These more holistic studies support the unified engram complex hypothesis for memory storage and have important implications for understanding dysfunctional engrams in the context of human disease.
Assuntos
Encéfalo , Hipocampo , Memória , Humanos , Memória/fisiologia , Animais , Encéfalo/fisiologia , Neurônios/metabolismo , Medo/fisiologiaRESUMO
Episodic memories are encoded by experience-activated neuronal ensembles that remain necessary and sufficient for recall. However, the temporal evolution of memory engrams after initial encoding is unclear. In this study, we employed computational and experimental approaches to examine how the neural composition and selectivity of engrams change with memory consolidation. Our spiking neural network model yielded testable predictions: memories transition from unselective to selective as neurons drop out of and drop into engrams; inhibitory activity during recall is essential for memory selectivity; and inhibitory synaptic plasticity during memory consolidation is critical for engrams to become selective. Using activity-dependent labeling, longitudinal calcium imaging and a combination of optogenetic and chemogenetic manipulations in mouse dentate gyrus, we conducted contextual fear conditioning experiments that supported our model's predictions. Our results reveal that memory engrams are dynamic and that changes in engram composition mediated by inhibitory plasticity are crucial for the emergence of memory selectivity.
Assuntos
Consolidação da Memória , Memória Episódica , Camundongos , Animais , Consolidação da Memória/fisiologia , Rememoração Mental/fisiologia , Neurônios/fisiologia , Medo/fisiologiaRESUMO
Identification of synaptic partners is a fundamental task for systems neuroscience. To date, few reliable techniques exist for whole brain labeling of downstream synaptic partners in a cell-type-dependent and monosynaptic manner. Herein, we describe a novel monosynaptic anterograde tracing system based on the deletion of the gene UL6 from the genome of a cre-dependent version of the anterograde Herpes Simplex Virus 1 strain H129. Given that this knockout blocks viral genome packaging and thus viral spread, we reasoned that co-infection of a HSV H129 ΔUL6 virus with a recombinant adeno-associated virus expressing UL6 in a cre-dependent manner would result in monosynaptic spread from target cre-expressing neuronal populations. Application of this system to five nonreciprocal neural circuits resulted in labeling of neurons in expected projection areas. While some caveats may preclude certain applications, this system provides a reliable method to label postsynaptic partners in a brain-wide fashion.
Assuntos
Herpesvirus Humano 1 , Herpesvirus Humano 1/genética , Neurônios , EncéfaloRESUMO
In this issue of Neuron, Sun et al. (2022) identify a neuronal subpopulation in the medial paralemniscal nucleus that underlies repetitive self-grooming. Through their projections to dopamine neurons in the ventral tegmental area, this subpopulation also drives reward and alleviates anxiety.
Assuntos
Prazer , Área Tegmentar Ventral , Animais , Área Tegmentar Ventral/fisiologia , Neurônios Dopaminérgicos/fisiologia , RecompensaRESUMO
Although bradykinesia, tremor and rigidity are the hallmark motor defects in patients with Parkinson's disease (PD), patients also experience motor learning impairments and non-motor symptoms such as depression1. The neural circuit basis for these different symptoms of PD are not well understood. Although current treatments are effective for locomotion deficits in PD2,3, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking4-6. Here we found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN) and nucleus accumbens (NAc). Whereas PFâCPu and PFâSTN circuits are critical for locomotion and motor learning, respectively, inhibition of the PFâNAc circuit induced a depression-like state. Whereas chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation (LTP) at PFâSTN synapses restored motor learning behaviour in an acute mouse model of PD. Furthermore, activation of NAc-projecting PF neurons rescued depression-like phenotypes. Further, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.
Assuntos
Afeto , Destreza Motora , Vias Neurais , Doença de Parkinson , Tálamo , Animais , Modelos Animais de Doenças , Aprendizagem , Locomoção , Potenciação de Longa Duração , Camundongos , Neurônios/fisiologia , Núcleo Accumbens , Optogenética , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologia , Doença de Parkinson/terapia , Putamen , Receptores Nicotínicos , Núcleo Subtalâmico , Sinapses , Tálamo/citologia , Tálamo/patologiaRESUMO
Alterations in the structure and functional connectivity of anterior thalamic nuclei (ATN) have been linked to reduced cognition during aging. However, ATN circuits that contribute to higher cognitive functions remain understudied. We found that the anteroventral (AV) subdivision of ATN is necessary specifically during the maintenance phase of a spatial working memory task. This function engages the AVâparasubiculum (PaS)âentorhinal cortex (EC) circuit. Aged mice showed a deficit in spatial working memory, which was associated with a decrease in the excitability of AV neurons. Activation of AV neurons or the AVâPaS circuit in aged mice was sufficient to rescue their working memory performance. Furthermore, rescued aged mice showed improved behavior-induced neuronal activity in prefrontal cortex (PFC), a critical site for working memory processes. Although the direct activation of PFC neurons in aged mice also rescued their working memory performance, we found that these animals exhibited increased levels of anxiety, which was not the case for AVâPaS circuit manipulations in aged mice. These results suggest that targeting AV thalamus in aging may not only be beneficial for cognitive functions but that this approach may have fewer unintended effects compared to direct PFC manipulations.
Assuntos
Núcleos Anteriores do Tálamo , Animais , Núcleos Anteriores do Tálamo/fisiologia , Cognição , Transtornos da Memória , Memória de Curto Prazo/fisiologia , Camundongos , Vias Neurais/fisiologia , NeurôniosRESUMO
Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos+ brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage.
Assuntos
Mapeamento Encefálico , Memória , Animais , Encéfalo , Medo/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , CamundongosRESUMO
The thalamus engages in various functions including sensory processing, attention, decision making and memory. Classically, this diversity of function has been attributed to the nuclear organization of the thalamus, with each nucleus performing a well-defined function. Here, we highlight recent studies that used state-of-the-art expression profiling, which have revealed gene expression gradients at the single-cell level within and across thalamic nuclei. These gradients, combined with anatomical tracing and physiological analyses, point to previously unappreciated heterogeneity and redefine thalamic units of function on the basis of unique input-output connectivity patterns and gene expression. We propose that thalamic subnetworks, defined by the intersection of genetics, connectivity and computation, provide a more appropriate level of functional description; this notion is supported by behavioral phenotypes resulting from appropriately tailored perturbations. We provide several examples of thalamic subnetworks and suggest how this new perspective may both propel progress in basic neuroscience and reveal unique targets with therapeutic potential.
Assuntos
Núcleos Talâmicos , Tálamo , Atenção/fisiologia , Vias Neurais/fisiologia , Núcleos Talâmicos/fisiologia , Tálamo/fisiologiaRESUMO
Neuropsychiatric disorders are often accompanied by cognitive impairments/intellectual disability (ID). It is not clear whether there are converging mechanisms underlying these debilitating impairments. We found that many autism and schizophrenia risk genes are expressed in the anterodorsal subdivision (AD) of anterior thalamic nuclei, which has reciprocal connectivity with learning and memory structures. CRISPR-Cas9 knockdown of multiple risk genes selectively in AD thalamus led to memory deficits. While the AD is necessary for contextual memory encoding, the neighboring anteroventral subdivision (AV) regulates memory specificity. These distinct functions of AD and AV are mediated through their projections to retrosplenial cortex, using differential mechanisms. Furthermore, knockdown of autism and schizophrenia risk genes PTCHD1, YWHAG, or HERC1 from AD led to neuronal hyperexcitability, and normalization of hyperexcitability rescued memory deficits in these models. This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models.
Assuntos
Núcleos Anteriores do Tálamo/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Vias Neurais/fisiopatologia , Núcleos Talâmicos/fisiopatologia , Animais , Núcleos Anteriores do Tálamo/fisiologia , Córtex Cerebral/fisiopatologia , Cognição/fisiologia , Camundongos , Vias Neurais/fisiologia , Núcleos Talâmicos/fisiologiaRESUMO
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.
Assuntos
Giro Denteado/citologia , Potenciais da Membrana/fisiologia , Rememoração Mental/fisiologia , Neurônios/fisiologia , Animais , Anisomicina/farmacologia , Proteínas de Bactérias/genética , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Condicionamento Psicológico/fisiologia , Doxiciclina/farmacologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Imidazóis/farmacologia , Proteínas Luminescentes/genética , Potenciais da Membrana/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Fenantrolinas/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Transdução GenéticaRESUMO
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.
Assuntos
Amnésia Retrógrada/fisiopatologia , Rememoração Mental/fisiologia , Neurônios/metabolismo , Optogenética/psicologia , Animais , Comportamento Animal , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Aprendizagem , Masculino , Memória de Longo Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Próteses e Implantes , Coluna Vertebral/patologia , Sinapses/metabolismoRESUMO
The formation and retrieval of a memory is thought to be accomplished by activation and reactivation, respectively, of the memory-holding cells (engram cells) by a common set of neural circuits, but this hypothesis has not been established. The medial temporal-lobe system is essential for the formation and retrieval of episodic memory for which individual hippocampal subfields and entorhinal cortex layers contribute by carrying out specific functions. One subfield whose function is poorly known is the subiculum. Here, we show that dorsal subiculum and the circuit, CA1 to dorsal subiculum to medial entorhinal cortex layer 5, play a crucial role selectively in the retrieval of episodic memories. Conversely, the direct CA1 to medial entorhinal cortex layer 5 circuit is essential specifically for memory formation. Our data suggest that the subiculum-containing detour loop is dedicated to meet the requirements associated with recall such as rapid memory updating and retrieval-driven instinctive fear responses.
Assuntos
Córtex Entorrinal/metabolismo , Hipocampo/metabolismo , Memória Episódica , Vias Neurais , Animais , Corticosterona/metabolismo , Córtex Entorrinal/citologia , Expressão Gênica , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , OptogenéticaRESUMO
Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation have thus far been unknown. We found that neocortical prefrontal memory engram cells, which are critical for remote contextual fear memory, were rapidly generated during initial learning through inputs from both the hippocampal-entorhinal cortex network and the basolateral amygdala. After their generation, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time. Whereas hippocampal engram cells gradually became silent with time, engram cells in the basolateral amygdala, which were necessary for fear memory, were maintained. Our data provide new insights into the functional reorganization of engrams and circuits underlying systems consolidation of memory.
Assuntos
Córtex Entorrinal/fisiologia , Hipocampo/fisiologia , Consolidação da Memória/fisiologia , Memória Episódica , Córtex Pré-Frontal/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Condicionamento Psicológico , Medo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/fisiologia , Plasticidade Neuronal , Córtex Pré-Frontal/citologiaRESUMO
The medial temporal lobe, including the hippocampus, has been implicated in social memory. However, it remains unknown which parts of these brain regions and their circuits hold social memory. Here, we show that ventral hippocampal CA1 (vCA1) neurons of a mouse and their projections to nucleus accumbens (NAc) shell play a necessary and sufficient role in social memory. Both the proportion of activated vCA1 cells and the strength and stability of the responding cells are greater in response to a familiar mouse than to a previously unencountered mouse. Optogenetic reactivation of vCA1 neurons that respond to the familiar mouse enabled memory retrieval and the association of these neurons with unconditioned stimuli. Thus, vCA1 neurons and their NAc shell projections are a component of the storage site of social memory.
Assuntos
Região CA1 Hipocampal/fisiologia , Ventrículos Cerebrais/fisiologia , Rememoração Mental/fisiologia , Células Piramidais/fisiologia , Comportamento Social , Animais , Região CA1 Hipocampal/citologia , Ventrículos Cerebrais/citologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Núcleo Accumbens/citologia , Núcleo Accumbens/fisiologia , OptogenéticaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.
Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Giro Denteado/citologia , Giro Denteado/fisiologia , Modelos Animais de Doenças , Memória de Longo Prazo/fisiologia , Envelhecimento , Amnésia/patologia , Amnésia/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Giro Denteado/patologia , Giro Denteado/fisiopatologia , Intervenção Médica Precoce , Humanos , Potenciação de Longa Duração , Masculino , Memória Episódica , Camundongos , Camundongos Transgênicos , Optogenética , Placa Amiloide , Presenilina-1/genética , Sinapses/metabolismo , Transgenes/genética , Proteínas tau/genéticaRESUMO
A great deal of experimental investment is directed towards questions regarding the mechanisms of memory storage. Such studies have traditionally been restricted to investigation of the anatomical structures, physiological processes, and molecular pathways necessary for the capacity of memory storage, and have avoided the question of how individual memories are stored in the brain. Memory engram technology allows the labeling and subsequent manipulation of components of specific memory engrams in particular brain regions, and it has been established that cell ensembles labeled by this method are both sufficient and necessary for memory recall. Recent research has employed this technology to probe fundamental questions of memory consolidation, differentiating between mechanisms of memory retrieval from the true neurobiology of memory storage.
Assuntos
Amnésia Retrógrada/fisiopatologia , Genes Precoces/fisiologia , Memória/fisiologia , Rememoração Mental/fisiologia , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Optogenética/métodos , Amnésia Retrógrada/metabolismo , Animais , Genes Precoces/genética , Humanos , Neurônios/metabolismoRESUMO
Memory consolidation is the process by which a newly formed and unstable memory transforms into a stable long-term memory. It is unknown whether the process of memory consolidation occurs exclusively through the stabilization of memory engrams. By using learning-dependent cell labeling, we identified an increase of synaptic strength and dendritic spine density specifically in consolidated memory engram cells. Although these properties are lacking in engram cells under protein synthesis inhibitor-induced amnesia, direct optogenetic activation of these cells results in memory retrieval, and this correlates with retained engram cell-specific connectivity. We propose that a specific pattern of connectivity of engram cells may be crucial for memory information storage and that strengthened synapses in these cells critically contribute to the memory retrieval process.
Assuntos
Amnésia Retrógrada/fisiopatologia , Dendritos/fisiologia , Memória de Longo Prazo/fisiologia , Amnésia Retrógrada/induzido quimicamente , Tonsila do Cerebelo/química , Tonsila do Cerebelo/fisiopatologia , Animais , Condicionamento Clássico , Dendritos/química , Dendritos/patologia , Giro Denteado/química , Giro Denteado/patologia , Giro Denteado/fisiopatologia , Corantes Fluorescentes/análise , Proteínas Luminescentes/análise , Camundongos , Plasticidade Neuronal/fisiologia , Inibidores da Síntese de Proteínas/farmacologia , Coloração e Rotulagem , Sinapses/fisiologia , Proteína Vermelha FluorescenteRESUMO
Animals display a repertoire of different social behaviours. Appropriate behavioural responses depend on sensory input received during social interactions. In mice, social behaviour is driven by pheromones, chemical signals that encode information related to age, sex and physiological state. However, although mice show different social behaviours towards adults, juveniles and neonates, sensory cues that enable specific recognition of juvenile mice are unknown. Here we describe a juvenile pheromone produced by young mice before puberty, termed exocrine-gland secreting peptide 22 (ESP22). ESP22 is secreted from the lacrimal gland and released into tears of 2- to 3-week-old mice. Upon detection, ESP22 activates high-affinity sensory neurons in the vomeronasal organ, and downstream limbic neurons in the medial amygdala. Recombinant ESP22, painted on mice, exerts a powerful inhibitory effect on adult male mating behaviour, which is abolished in knockout mice lacking TRPC2, a key signalling component of the vomeronasal organ. Furthermore, knockout of TRPC2 or loss of ESP22 production results in increased sexual behaviour of adult males towards juveniles, and sexual responses towards ESP22-deficient juveniles are suppressed by ESP22 painting. Thus, we describe a pheromone of sexually immature mice that controls an innate social behaviour, a response pathway through the accessory olfactory system and a new role for vomeronasal organ signalling in inhibiting sexual behaviour towards young. These findings provide a molecular framework for understanding how a sensory system can regulate behaviour.