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Nature Oct 2021Mounting evidence shows that dopamine in the striatum is critically involved in reward-based reinforcement learning. However, it remains unclear how dopamine reward...
Mounting evidence shows that dopamine in the striatum is critically involved in reward-based reinforcement learning. However, it remains unclear how dopamine reward signals influence the entorhinal-hippocampal circuit, another brain network that is crucial for learning and memory. Here, using cell-type-specific electrophysiological recording, we show that dopamine signals from the ventral tegmental area and substantia nigra control the encoding of cue-reward association rules in layer 2a fan cells of the lateral entorhinal cortex (LEC). When mice learned novel olfactory cue-reward associations using a pre-learned association rule, spike representations of LEC fan cells grouped newly learned rewarded cues with a pre-learned rewarded cue, but separated them from a pre-learned unrewarded cue. Optogenetic inhibition of fan cells impaired the learning of new associations while sparing the retrieval of pre-learned memory. Using fibre photometry, we found that dopamine sends novelty-induced reward expectation signals to the LEC. Inhibition of LEC dopamine signals disrupted the associative encoding of fan cells and impaired learning performance. These results suggest that LEC fan cells represent a cognitive map of abstract task rules, and that LEC dopamine facilitates the incorporation of new memories into this map.
Topics: Animals; Anticipation, Psychological; Cues; Dopamine; Entorhinal Cortex; Female; Male; Memory; Mice; Mice, Inbred C57BL; Pyramidal Cells; Reward
PubMed: 34552245
DOI: 10.1038/s41586-021-03948-8 -
Cell Aug 2017The 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...
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.
Topics: Animals; Corticosterone; Entorhinal Cortex; Gene Expression; Hippocampus; Male; Memory, Episodic; Mice; Mice, Inbred C57BL; Neural Pathways; Neurons; Optogenetics
PubMed: 28823555
DOI: 10.1016/j.cell.2017.07.013 -
Hippocampus Jun 2015The discoveries of "place cells" in the hippocampus and "grid cells" in the entorhinal cortex are landmark achievements in relating behavior to neural activity,...
The discoveries of "place cells" in the hippocampus and "grid cells" in the entorhinal cortex are landmark achievements in relating behavior to neural activity, permitting analysis of a powerful system for spatial representation in the brain. The contributions of this work include not only the empirical findings but also the approach this work pioneered of examining neural activity in complex behaviors with real ecological validity in freely moving animals, and of attempting to place the findings in the larger context of how the neural representations of space are used in service of real-world behavior, namely what the Nobel committee described as permitting us to "navigate our way through a complex environment." These discoveries and approaches have had far-ranging impact on and implications for work in human cognitive neuroscience, where we see (1) confirmation in humans that the hippocampus and overlying MTL cortex are critically engaged in supporting a relational representation of space, and that it can be used for flexible spatial navigation and (2) evidence that these regions are also critically involved in aspects of relational memory not limited to space, and in the flexible use of hippocampal memory extending beyond spatial navigation. Recent work, using tasks that emphasize the requirement for the active use of memory in online processing, just as spatial navigation has long placed such a requirement on rodents, suggests that the hippocampus and related MTL cortex can support the navigating of environments even more complex than what is needed in spatial navigation. It allows us to use memory in guiding upcoming actions and choices to act optimally in and on the world, permitting us to navigate life in all its beautiful complexity.
Topics: Animals; Entorhinal Cortex; Hippocampus; Humans; Models, Neurological; Neural Pathways; Neurosciences; Nobel Prize; Space Perception; Spatial Behavior
PubMed: 25787273
DOI: 10.1002/hipo.22443 -
International Journal of Molecular... Oct 2021Depression is characterized by impairments in adult neurogenesis. Reduced hippocampal function, which is suggestive of neurogenesis impairments, is associated with... (Review)
Review
Depression is characterized by impairments in adult neurogenesis. Reduced hippocampal function, which is suggestive of neurogenesis impairments, is associated with depression-related phenotypes. As adult neurogenesis operates in an activity-dependent manner, disruption of hippocampal neurogenesis in depression may be a consequence of neural circuitry impairments. In particular, the entorhinal cortex is known to have a regulatory effect on the neural circuitry related to hippocampal function and adult neurogenesis. However, a comprehensive understanding of how disruption of the neural circuitry can lead to neurogenesis impairments in depression remains unclear with respect to the regulatory role of the entorhinal cortex. This review highlights recent findings suggesting neural circuitry-regulated neurogenesis, with a focus on the potential role of the entorhinal cortex in hippocampal neurogenesis in depression-related cognitive and emotional phenotypes. Taken together, these findings may provide a better understanding of the entorhinal cortex-regulated hippocampal neurogenesis model of depression.
Topics: Adult; Animals; Cognition; Depressive Disorder, Major; Emotions; Entorhinal Cortex; Hippocampus; Humans; Neurogenesis
PubMed: 34769155
DOI: 10.3390/ijms222111725 -
The Journal of Comparative Neurology Mar 2021The anterior cingulate cortex (ACC) is important for decision-making as it integrates motor plans with affective and contextual limbic information. Disruptions in these...
The anterior cingulate cortex (ACC) is important for decision-making as it integrates motor plans with affective and contextual limbic information. Disruptions in these networks have been observed in depression, bipolar disorder, and post-traumatic stress disorder. Yet, overlap of limbic and motor connections within subdivisions of the ACC is not well understood. Hence, we administered a combination of retrograde and anterograde tracers into structures important for contextual memories (entorhinal cortex), affective processing (amygdala), and motor planning (dorsal premotor cortex) to assess overlap of labeled projection neurons from (outputs) and axon terminals to (inputs) the ACC of adult rhesus monkeys (Macaca mulatta). Our data show that entorhinal and dorsal premotor cortical (dPMC) connections are segregated across ventral (A25, A24a) and dorsal (A24b,c) subregions of the ACC, while amygdalar connections are more evenly distributed across subregions. Among all areas, the rostral ACC (A32) had the lowest relative density of connections with all three regions. In the ventral ACC, entorhinal and amygdalar connections strongly overlap across all layers, especially in A25. In the dorsal ACC, outputs to dPMC and the amygdala strongly overlap in deep layers. However, dPMC input to the dorsal ACC was densest in deep layers, while amygdalar inputs predominantly localized in upper layers. These connection patterns are consistent with diverse roles of the dorsal ACC in motor evaluation and the ventral ACC in affective and contextual memory. Further, distinct laminar circuits suggest unique interactions within specific ACC compartments that are likely important for the temporal integration of motor and limbic information during flexible goal-directed behavior.
Topics: Amygdala; Animals; Entorhinal Cortex; Female; Gyrus Cinguli; Macaca mulatta; Male; Neural Pathways; Prefrontal Cortex
PubMed: 32677044
DOI: 10.1002/cne.24986 -
Journal of Neurophysiology Jun 2018Following the groundbreaking discovery of grid cells, the medial entorhinal cortex (MEC) has become the focus of intense anatomical, physiological, and computational... (Review)
Review
Following the groundbreaking discovery of grid cells, the medial entorhinal cortex (MEC) has become the focus of intense anatomical, physiological, and computational investigations. Whether and how grid activity maps onto cell types and cortical architecture is still an open question. Fundamental similarities in microcircuits, function, and connectivity suggest a homology between rodent MEC and human posteromedial entorhinal cortex. Both are specialized for spatial processing and display similar cellular organization, consisting of layer 2 pyramidal/calbindin cell patches superimposed on scattered stellate neurons. Recent data indicate the existence of a further nonoverlapping modular system (zinc patches) within the superficial MEC layers. Zinc and calbindin patches have been shown to receive largely segregated inputs from the presubiculum and parasubiculum. Grid cells are also clustered in the MEC, and we discuss possible structure-function schemes on how grid activity could map onto cortical patch systems. We hypothesize that in the superficial layers of the MEC, anatomical location can be predictive of function; thus relating functional properties and neuronal morphologies to the cortical modules will be necessary for resolving how grid activity maps onto cortical architecture. Imaging or cell identification approaches in freely moving animals will be required for testing this hypothesis.
Topics: Animals; Entorhinal Cortex; Grid Cells; Humans
PubMed: 29513150
DOI: 10.1152/jn.00574.2017 -
Proceedings of the National Academy of... Feb 2022The medial entorhinal cortex (MEC) creates a map of local space, based on the firing patterns of grid, head-direction (HD), border, and object-vector (OV) cells. How...
The medial entorhinal cortex (MEC) creates a map of local space, based on the firing patterns of grid, head-direction (HD), border, and object-vector (OV) cells. How these cell types are organized anatomically is debated. In-depth analysis of this question requires collection of precise anatomical and activity data across large populations of neurons during unrestrained behavior, which neither electrophysiological nor previous imaging methods fully afford. Here, we examined the topographic arrangement of spatially modulated neurons in the superficial layers of MEC and adjacent parasubiculum using miniaturized, portable two-photon microscopes, which allow mice to roam freely in open fields. Grid cells exhibited low levels of co-occurrence with OV cells and clustered anatomically, while border, HD, and OV cells tended to intermingle. These data suggest that grid cell networks might be largely distinct from those of border, HD, and OV cells and that grid cells exhibit strong coupling among themselves but weaker links to other cell types.
Topics: Animals; Brain Mapping; Entorhinal Cortex; Male; Mice; Microscopy; Miniaturization; Motor Activity; Neurons
PubMed: 35135885
DOI: 10.1073/pnas.2121655119 -
The Journal of Neuroscience : the... Jun 2021The postrhinal area (POR) is a known center for integrating spatial with nonspatial visual information and a possible hub for influencing landmark navigation by...
The postrhinal area (POR) is a known center for integrating spatial with nonspatial visual information and a possible hub for influencing landmark navigation by affective input from the amygdala. This may involve specific circuits within muscarinic acetylcholine receptor 2 (M2)-positive (M2) or M2 modules of POR that associate inputs from the thalamus, cortex, and amygdala, and send outputs to the entorhinal cortex. Using anterograde and retrograde labeling with conventional and viral tracers in male and female mice, we found that all higher visual areas of the ventral cortical stream project to the amygdala, while such inputs are absent from primary visual cortex and dorsal stream areas. Unexpectedly for the presumed salt-and-pepper organization of mouse extrastriate cortex, tracing results show that inputs from the dorsal lateral geniculate nucleus and lateral posterior nucleus were spatially clustered in layer 1 (L1) and overlapped with M2 patches of POR. In contrast, input from the amygdala to L1 of POR terminated in M2 interpatches. Importantly, the amygdalocortical input to M2 interpatches in L1 overlapped preferentially with spatially clustered apical dendrites of POR neurons projecting to amygdala and entorhinal area lateral, medial (ENTm). The results suggest that subnetworks in POR, used to build spatial maps for navigation, do not receive direct thalamocortical M2 patch-targeting inputs. Instead, they involve local networks of M2 interpatches, which are influenced by affective information from the amygdala and project to ENTm, whose cells respond to visual landmark cues for navigation. A central purpose of visual object recognition is identifying the salience of objects and approaching or avoiding them. However, it is not currently known how the visual cortex integrates the multiple streams of information, including affective and navigational cues, which are required to accomplish this task. We find that in a higher visual area, the postrhinal cortex, the cortical sheet is divided into interdigitating modules receiving distinct inputs from visual and emotion-related sources. One of these modules is preferentially connected with the amygdala and provides outputs to entorhinal cortex, constituting a processing stream that may assign emotional salience to objects and landmarks for the guidance of goal-directed navigation.
Topics: Amygdala; Animals; Entorhinal Cortex; Female; Male; Mice; Mice, Inbred C57BL; Neural Pathways; Spatial Navigation; Visual Cortex
PubMed: 33849948
DOI: 10.1523/JNEUROSCI.2185-20.2021 -
Neural Plasticity 2008
Topics: Animals; Electroencephalography; Entorhinal Cortex; Humans; Memory; Neuronal Plasticity; Neurotransmitter Agents; Synaptic Potentials
PubMed: 19132097
DOI: 10.1155/2008/314785 -
Philosophical Transactions of the Royal... Feb 2014Neurons in the medial entorhinal cortex fire action potentials at regular spatial intervals, creating a striking grid-like pattern of spike rates spanning the whole... (Review)
Review
Neurons in the medial entorhinal cortex fire action potentials at regular spatial intervals, creating a striking grid-like pattern of spike rates spanning the whole environment of a navigating animal. This remarkable spatial code may represent a neural map for path integration. Recent advances using patch-clamp recordings from entorhinal cortex neurons in vitro and in vivo have revealed how the microcircuitry in the medial entorhinal cortex may contribute to grid cell firing patterns, and how grid cells may transform synaptic inputs into spike output during firing field crossings. These new findings provide key insights into the ingredients necessary to build a grid cell.
Topics: Action Potentials; Animals; Entorhinal Cortex; Mice; Models, Neurological; Neurons; Patch-Clamp Techniques; Spatial Behavior
PubMed: 24366132
DOI: 10.1098/rstb.2012.0520