RESUMO
Spontaneous neural activity sequences are generated by the brain in the absence of external input 1-12 , yet how they are produced remains unknown. During immobility, hippocampal replay sequences depict spatial paths related to the animal's past experience or predicted future 13 . By recording from large ensembles of hippocampal place cells 14 in combination with optogenetic manipulation of cortical input in freely behaving rats, we show here that the selection of hippocampal replay is governed by a novel self-avoidance principle. Following movement cessation, replay of the animal's past path is strongly avoided, while replay of the future path predominates. Moreover, when the past and future paths overlap, early replays avoid both and depict entirely different trajectories. Further, replays avoid self-repetition, on a shorter timescale compared to the avoidance of previous behavioral trajectories. Eventually, several seconds into the stopping period, replay of the past trajectory dominates. This temporal organization contrasts with established and recent predictions 9,10,15,16 but is well-recapitulated by a symmetry-breaking attractor model of sequence generation in which individual neurons adapt their firing rates over time 26-35 . However, while the model is sufficient to produce avoidance of recently traversed or reactivated paths, it requires an additional excitatory input into recently activated cells to produce the later window of past-dominance. We performed optogenetic perturbations to demonstrate that this input is provided by medial entorhinal cortex, revealing its role in maintaining a memory of past experience that biases hippocampal replay. Together, these data provide specific evidence for how hippocampal replays are generated.
RESUMO
Neural circuits generate representations of the external world from multiple information streams. The navigation system provides an exceptional lens through which we may gain insights about how such computations are implemented. Neural circuits in the medial temporal lobe construct a map-like representation of space that supports navigation. This computation integrates multiple sensory cues, and, in addition, is thought to require cues related to the individual's movement through the environment. Here, we identify multiple self-motion signals, related to the position and velocity of the head and eyes, encoded by neurons in a key node of the navigation circuitry of mice, the medial entorhinal cortex (MEC). The representation of these signals is highly integrated with other cues in individual neurons. Such information could be used to compute the allocentric location of landmarks from visual cues and to generate internal representations of space.
Assuntos
Córtex Entorrinal/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Navegação Espacial/fisiologia , Percepção Visual/fisiologia , Algoritmos , Animais , Sinais (Psicologia) , Córtex Entorrinal/citologia , Movimentos Oculares/fisiologia , Feminino , Movimentos da Cabeça/fisiologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Rede Nervosa/citologiaRESUMO
The entorhinal cortex contains neurons that represent self-location, including grid cells that fire in periodic locations and velocity signals that encode running speed and head direction. Although the size and shape of the environment influence grid patterns, whether entorhinal velocity signals are equally influenced or provide a universal metric for self-motion across environments remains unknown. Here we report that speed cells rescale after changes to the size and shape of the environment. Moreover, head direction cells reorganize in an experience-dependent manner to align with the axis of environmental change. A knockout mouse model allows dissociation of the coordination between cell types, with grid and speed cells, but not head direction cells, responding in concert to environmental change. These results point to malleability in the coding features of multiple entorhinal cell types and have implications for which cell types contribute to the velocity signal used by computational models of grid cells.
Assuntos
Córtex Entorrinal/fisiologia , Células de Grade/fisiologia , Modelos Neurológicos , Percepção Espacial/fisiologia , Navegação Espacial/fisiologia , Animais , Simulação por Computador , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
To guide navigation, the nervous system integrates multisensory self-motion and landmark information. We dissected how these inputs generate spatial representations by recording entorhinal grid, border and speed cells in mice navigating virtual environments. Manipulating the gain between the animal's locomotion and the visual scene revealed that border cells responded to landmark cues while grid and speed cells responded to combinations of locomotion, optic flow and landmark cues in a context-dependent manner, with optic flow becoming more influential when it was faster than expected. A network model explained these results by revealing a phase transition between two regimes in which grid cells remain coherent with or break away from the landmark reference frame. Moreover, during path-integration-based navigation, mice estimated their position following principles predicted by our recordings. Together, these results provide a theoretical framework for understanding how landmark and self-motion cues combine during navigation to generate spatial representations and guide behavior.
Assuntos
Sinais (Psicologia) , Córtex Entorrinal/fisiologia , Movimento/fisiologia , Orientação/fisiologia , Percepção Espacial/fisiologia , Animais , Córtex Entorrinal/citologia , Potenciais Evocados/fisiologia , Feminino , Locomoção/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Redes Neurais de Computação , Neurônios/classificação , Desempenho Psicomotor/fisiologia , Realidade Virtual , Percepção Visual/fisiologiaRESUMO
The discovery of place cells provided fundamental insight into the neural basis by which the hippocampus encodes spatial memories and supports navigation and prompted the development of computational models to explain the emergence of their spatial selectively. Many such works posit that input from entorhinal grid cells is critical to the formation of place fields, a prediction that has received mixed experimental support. Potentially reconciling seemingly conflicting findings is recent work indicating that subpopulations of pyramidal neurons are functionally distinct and may be driven to varying degrees by different inputs. Additionally, new studies have demonstrated that hippocampal principal neurons encode a myriad of features extending beyond current position. Here, we highlight recent evidence for how extensive heterogeneity in connectivity and genetic expression could interact with membrane biophysics to enable place cells to encode a diverse range of stimuli. These recent findings highlight the need for more computational models that integrate these heterogeneous features of hippocampal principal neurons.
Assuntos
Hipocampo/fisiologia , Modelos Neurológicos , Percepção Espacial/fisiologia , Animais , Simulação por Computador , Hipocampo/citologia , Humanos , Neurônios/fisiologiaRESUMO
Medial entorhinal cortex (MEC) grid cells fire at regular spatial intervals and project to the hippocampus, where place cells are active in spatially restricted locations. One feature of the grid population is the increase in grid spatial scale along the dorsal-ventral MEC axis. However, the difficulty in perturbing grid scale without impacting the properties of other functionally defined MEC cell types has obscured how grid scale influences hippocampal coding and spatial memory. Here we use a targeted viral approach to knock out HCN1 channels selectively in MEC, causing the grid scale to expand while leaving other MEC spatial and velocity signals intact. Grid scale expansion resulted in place scale expansion in fields located far from environmental boundaries, reduced long-term place field stability and impaired spatial learning. These observations, combined with simulations of a grid-to-place cell model and position decoding of place cells, illuminate how grid scale impacts place coding and spatial memory.
Assuntos
Mapeamento Encefálico , Córtex Entorrinal/citologia , Células de Grade/fisiologia , Vias Neurais/fisiologia , Células de Lugar/fisiologia , Percepção Espacial/fisiologia , Potenciais de Ação/genética , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Eletroencefalografia , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/citologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/deficiência , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Neurológicos , Fosfopiruvato Hidratase/metabolismo , Canais de Potássio/deficiência , Canais de Potássio/genéticaRESUMO
The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses.
Assuntos
Acetilcolina/metabolismo , Comportamento Animal/fisiologia , Neurônios Colinérgicos/metabolismo , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica/fisiologia , Animais , Neurônios Colinérgicos/citologia , Halorrodopsinas/biossíntese , Halorrodopsinas/genética , Camundongos , Camundongos Transgênicos , Córtex Pré-Frontal/citologiaRESUMO
Reductions in the capacity of the human choline transporter (SLC5A7, CHT) have been hypothesized to diminish cortical cholinergic neurotransmission, leading to risk for cognitive and mood disorders. To determine the acetylcholine (ACh) release capacity of cortical cholinergic projections in a mouse model of cholinergic hypofunction, the CHT+/- mouse, we assessed extracellular ACh levels while mice performed an operant sustained attention task (SAT). We found that whereas SAT-performance-associated increases in extracellular ACh levels of CHT+/- mice were significantly attenuated relative to wildtype littermates, performance on the SAT was normal. Tetrodotoxin-induced blockade of neuronal excitability reduced both dialysate ACh levels and SAT performance similarly in both genotypes. Likewise, lesions of cholinergic neurons abolished SAT performance in both genotypes. However, cholinergic activation remained more vulnerable to the reverse-dialyzed muscarinic antagonist atropine in CHT+/- mice. Additionally, CHT+/- mice displayed greater SAT-disrupting effects of reverse dialysis of the nAChR antagonist mecamylamine. Receptor binding assays revealed a higher density of α4ß2* nAChRs in the cortex of CHT+/- mice compared to controls. These findings reveal compensatory mechanisms that, in the context of moderate cognitive challenges, can overcome the performance deficits expected from the significantly reduced ACh capacity of CHT+/- cholinergic terminals. Further analyses of molecular and functional compensations in the CHT+/- model may provide insights into both risk and resiliency factors involved in cognitive and mood disorders.
Assuntos
Acetilcolina/metabolismo , Atenção/fisiologia , Proteínas de Membrana Transportadoras/genética , Alcaloides/farmacocinética , Animais , Atropina/farmacologia , Atenção/efeitos dos fármacos , Azocinas/farmacocinética , Antagonistas Colinérgicos/farmacologia , Condicionamento Operante , Feminino , Humanos , Masculino , Mecamilamina/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica/efeitos dos fármacos , Quinolizinas/farmacocinética , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Trítio/farmacocinéticaRESUMO
Behavioural states in mammals, such as the anxious state, are characterized by several features that are coordinately regulated by diverse nervous system outputs, ranging from behavioural choice patterns to changes in physiology (in anxiety, exemplified respectively by risk-avoidance and respiratory rate alterations). Here we investigate if and how defined neural projections arising from a single coordinating brain region in mice could mediate diverse features of anxiety. Integrating behavioural assays, in vivo and in vitro electrophysiology, respiratory physiology and optogenetics, we identify a surprising new role for the bed nucleus of the stria terminalis (BNST) in the coordinated modulation of diverse anxiety features. First, two BNST subregions were unexpectedly found to exert opposite effects on the anxious state: oval BNST activity promoted several independent anxious state features, whereas anterodorsal BNST-associated activity exerted anxiolytic influence for the same features. Notably, we found that three distinct anterodorsal BNST efferent projections-to the lateral hypothalamus, parabrachial nucleus and ventral tegmental area-each implemented an independent feature of anxiolysis: reduced risk-avoidance, reduced respiratory rate, and increased positive valence, respectively. Furthermore, selective inhibition of corresponding circuit elements in freely moving mice showed opposing behavioural effects compared with excitation, and in vivo recordings during free behaviour showed native spiking patterns in anterodorsal BNST neurons that differentiated safe and anxiogenic environments. These results demonstrate that distinct BNST subregions exert opposite effects in modulating anxiety, establish separable anxiolytic roles for different anterodorsal BNST projections, and illustrate circuit mechanisms underlying selection of features for the assembly of the anxious state.