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Neuron Jul 2020Animals must discern important stimuli and place them onto their cognitive map of their environment. The neocortex conveys general representations of sensory events to...
Animals must discern important stimuli and place them onto their cognitive map of their environment. The neocortex conveys general representations of sensory events to the hippocampus, and the hippocampus is thought to classify and sharpen the distinctions between these events. We recorded populations of dentate gyrus granule cells (DG GCs) and lateral entorhinal cortex (LEC) neurons across days to understand how sensory representations are modified by experience. We found representations of odors in DG GCs that required synaptic input from the LEC. Odor classification accuracy in DG GCs correlated with future behavioral discrimination. In associative learning, DG GCs, more so than LEC neurons, changed their responses to odor stimuli, increasing the distance in neural representations between stimuli, responding more to the conditioned and less to the unconditioned odorant. Thus, with learning, DG GCs amplify the decodability of cortical representations of important stimuli, which may facilitate information storage to guide behavior.
Topics: Animals; Association Learning; Dentate Gyrus; Male; Mice; Mice, Inbred C57BL; Neurons; Olfactory Perception
PubMed: 32359400
DOI: 10.1016/j.neuron.2020.04.002 -
Hippocampus Oct 2022Because the dentate gyrus serves as the first site for information processing in the hippocampal trisynaptic circuit, it an important structure for the formation of...
Because the dentate gyrus serves as the first site for information processing in the hippocampal trisynaptic circuit, it an important structure for the formation of associative memories. Previous findings in rabbit had recorded populations of cells within dentate gyrus that may bridge the temporal gap between stimuli to support memory formation during trace eyeblink conditioning, an associative learning task. However, this previous work was unable to identify the types of cells demonstrating this type of activity. To explore these changes further, we did in vivo single-neuron recording in conjunction with physiological determination of cell types to investigate the functional role of granule cells, mossy cells, and interneurons in dentate gyrus during learning. Tetrode recordings were performed in young-adult mice during training on trace eyeblink conditioning, a hippocampal-dependent temporal associative memory task. Conditioned mice were able to successfully learn the task, with male mice learning at a faster rate than female mice. In the conditioned group, granule cells tended to show an increase in firing rate during conditioned stimulus presentation while mossy cells showed a decrease in firing rate during the trace interval and the unconditioned stimulus. Interestingly, populations of interneurons demonstrated learning-related increases and decreases in activity that began at onset of the conditioned stimulus and persisted through the trace interval. The current study also found a significant increase in theta power during stimuli presentation in conditioned animals, and this change in theta decreased over time. Ultimately, these data suggest unique involvement of granule cells, mossy cells, and interneurons in dentate gyrus in the formation of a trace associative memory. This work expands our knowledge of dentate gyrus function, helping to discern how aging and disease might disrupt this process.
Topics: Animals; Conditioning, Classical; Conditioning, Eyelid; Dentate Gyrus; Female; Hippocampus; Learning; Male; Mice; Neurons; Rabbits
PubMed: 36018285
DOI: 10.1002/hipo.23468 -
ELife Jan 2017Adult-born neurons are continually produced in the dentate gyrus but it is unclear whether synaptic integration of new neurons affects the pre-existing circuit. Here we...
Adult-born neurons are continually produced in the dentate gyrus but it is unclear whether synaptic integration of new neurons affects the pre-existing circuit. Here we investigated how manipulating neurogenesis in adult mice alters excitatory synaptic transmission to mature dentate neurons. Enhancing neurogenesis by conditional deletion of the pro-apoptotic gene in stem cells reduced excitatory postsynaptic currents (EPSCs) and spine density in mature neurons, whereas genetic ablation of neurogenesis increased EPSCs in mature neurons. Unexpectedly, we found that deletion in developing and mature dentate neurons increased EPSCs and prevented neurogenesis-induced synaptic suppression. Together these results show that neurogenesis modifies synaptic transmission to mature neurons in a manner consistent with a redistribution of pre-existing synapses to newly integrating neurons and that a non-apoptotic function of the Bax signaling pathway contributes to ongoing synaptic refinement within the dentate circuit.
Topics: Animals; Dentate Gyrus; Excitatory Postsynaptic Potentials; Mice; Nerve Net; Neurogenesis; Neurons; Synaptic Transmission
PubMed: 28135190
DOI: 10.7554/eLife.19886 -
International Journal of Molecular... Mar 2023Studies indicating the influence of masticatory dysfunction, due to a soft diet or lack of molars, on impairing spatial memory and learning have led to research about...
The Masticatory Activity Interference in Quantitative Estimation of CA1, CA3 and Dentate Gyrus Hippocampal Astrocytes of Aged Murine Models and under Environmental Stimulation.
Studies indicating the influence of masticatory dysfunction, due to a soft diet or lack of molars, on impairing spatial memory and learning have led to research about neuronal connections between areas and cell populations possibly affected. In this sense, with scarce detailed data on the subfields of hippocampus in dementia neurodegeneration, there is no information about astrocytic responses in its different layers. Thus, considering this context, the present study evaluated the effects of deprivation and rehabilitation of masticatory activity, aging, and environmental enrichment on the stereological quantification of hippocampal astrocytes from layers CA1, CA3, and DG. For this purpose, we examined mature (6-month-old; 6M), and aged (18-month-old; 18M) mice, subjected to distinct masticatory regimens and environments. Three different regimens of masticatory activity were applied: continuous normal mastication with hard pellets (HD); normal mastication followed by deprived mastication with equal periods of pellets followed by soft powder (HD/SD); or rehabilitated masticatory activity with equal periods of HD, followed by powder, followed by pellets (HD/SD/HD). Under each specific regimen, half of the animals were raised in standard cages (impoverished environment (IE)) and the other half in enriched cages (enriched environment (EE)), mimicking sedentary or active lifestyles. Microscopic stereological, systematic, and random sampling approaches with an optical dissector of GFAP-immunolabeled astrocytes were done, allowing for an astrocyte numerical estimate. Stratum moleculare and hilus, from the dentate gyrus (DG) and Strata Lacunosum-Moleculare, Oriens, and Radiatum, similarly to the dentate gyrus, showed no significant change in any of the investigated variables (age, diet, or environment) in these layers. However, in Stratum radiatum, it was possible to observe significant differences associated with diet regimens and age. Therefore, diet-related differences were found when the HD 18M IE group was compared to the HD/SD/HD 18-month-old group in the same environment (IE) ( = 0.007). In the present study, we present modulatory factors (masticatory function, environmental enrichment, and aging) for the differentiated quantitative laminar response in the hippocampal regions, suggesting other studies to read the plasticity and responsiveness of astrocytes, including the molecular background.
Topics: Mice; Animals; Astrocytes; Disease Models, Animal; Powders; Hippocampus; Dentate Gyrus
PubMed: 37047502
DOI: 10.3390/ijms24076529 -
Neuron Feb 2022In this issue of Neuron, Franjic et al. (2022) use a single-nuclei RNA sequencing approach that identified signatures of adult neurogenesis in mouse, pig, and macaque...
In this issue of Neuron, Franjic et al. (2022) use a single-nuclei RNA sequencing approach that identified signatures of adult neurogenesis in mouse, pig, and macaque dentate gyrus, but not in humans, adding to a growing body of evidence that this process is likely lost in humans.
Topics: Animals; Dentate Gyrus; Humans; Mice; Neurogenesis; Neurons; Swine
PubMed: 35114104
DOI: 10.1016/j.neuron.2022.01.004 -
Neuropharmacology Mar 2021Alterations in the function of prefrontal cortex (PFC) and hippocampus have been implicated in underlying the relapse to alcohol seeking behaviors in humans and animal...
Alterations in the function of prefrontal cortex (PFC) and hippocampus have been implicated in underlying the relapse to alcohol seeking behaviors in humans and animal models of moderate to severe alcohol use disorders (AUD). Here we used chronic intermittent ethanol vapor exposure (CIE), 21d protracted abstinence following CIE (21d AB), and re-exposure to one vapor session during protracted abstinence (re-exposure) to evaluate the effects of chronic ethanol exposure on basal synaptic function, neuronal excitability and expression of key synaptic proteins that play a role in neuronal excitability in the medial PFC (mPFC) and dentate gyrus (DG). CIE consistently enhanced excitability of layer 2/3 pyramidal neurons in the mPFC and granule cell neurons in the DG. In the DG, this effect persisted during 21d AB. Re-exposure did not enhance excitability, suggesting resistance to vapor-induced effects. Analysis of action potential kinetics revealed that altered afterhyperpolarization, rise time and decay time constants are associated with the altered excitability during CIE, 21d AB and re-exposure. Molecular adaptations that may underlie increases in neuronal excitability under these different conditions were identified. Quantitative polymerase chain reaction of large-conductance potassium (BK) channel subunit mRNA in PFC and DG tissue homogenates did not show altered expression patterns of BK subunits. Western blotting demonstrates enhanced phosphorylation of Ca⁺/calmodulin-dependent protein kinase II (CaMKII), and reduced phosphorylation of glutamate receptor GluN2A/2B subunits. These results suggest a novel relationship between activity of CaMKII and GluN receptors in the mPFC and DG, and neuronal excitability in these brain regions in the context of moderate to severe AUD.
Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Dentate Gyrus; Ethanol; Inhalation Exposure; Male; Neurons; Organ Culture Techniques; Prefrontal Cortex; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate
PubMed: 33333103
DOI: 10.1016/j.neuropharm.2020.108438 -
The Journal of Neuroscience : the... Mar 2021The dentate gyrus (DG) of the hippocampus is important for cognition and behavior. However, the circuits underlying these functions are unclear. DG mossy cells (MCs) are...
The dentate gyrus (DG) of the hippocampus is important for cognition and behavior. However, the circuits underlying these functions are unclear. DG mossy cells (MCs) are potentially important because of their excitatory synapses on the primary cell type, granule cells (GCs). However, MCs also activate GABAergic neurons, which inhibit GCs. We used viral delivery of designer receptors exclusively activated by designer drugs (DREADDs) in mice to implement a gain- and loss-of-function study of MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some, but not all, types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate early gene c-Fos to address whether DREADDs bidirectionally regulated MC or GC activity. We confirmed excitatory DREADDs increased MC c-Fos. However, there was no change in GC c-Fos, consistent with MC activation leading to GABAergic inhibition of GCs. In contrast, inhibitory DREADDs led to a large increase in GC c-Fos, consistent with a reduction in MC excitation of GABAergic neurons, and reduced inhibition of GCs. Together, these results suggest that MCs regulate anxiety and cognition in specific ways. We also raise the possibility that cognitive performance may be improved by reducing anxiety. The dentate gyrus (DG) has many important cognitive roles as well as being associated with affective behavior. This study addressed how a glutamatergic DG cell type called mossy cells (MCs) contributes to diverse behaviors, which is timely because it is known that MCs regulate the activity of the primary DG cell type, granule cells (GCs), but how MC activity influences behavior is unclear. We show, surprisingly, that activating MCs can lead to adverse behavioral outcomes, and inhibiting MCs have an opposite effect. Importantly, the results appeared to be task-dependent and showed that testing both sexes was important. Additional experiments indicated what MC and GC circuitry was involved. Together, the results suggest how MCs influence behaviors that involve the DG.
Topics: Animals; Anxiety; Behavior, Animal; Cognition; Dentate Gyrus; Female; Male; Mice; Mossy Fibers, Hippocampal
PubMed: 33472828
DOI: 10.1523/JNEUROSCI.1724-20.2021 -
Endocrinology and Metabolism (Seoul,... Apr 2022Developmental hypothyroidism impairs learning and memory in offspring, which depend on extensive neuronal circuits in the entorhinal cortex, together with the...
BACKGROUND
Developmental hypothyroidism impairs learning and memory in offspring, which depend on extensive neuronal circuits in the entorhinal cortex, together with the hippocampus and neocortex. The entorhinal-dentate gyrus pathway is the main entrance of memory circuits. We investigated whether developmental hypothyroidism impaired the morphological development of the entorhinal-dentate gyrus pathway.
METHODS
We examined the structure and function of the entorhinal-dentate gyrus pathway in response to developmental hypothyroidism induced using 2-mercapto-1-methylimidazole.
RESULTS
1,1´-Dioctadecyl-3,3,3´,3´-tetramethylindocarbocyanine perchlorate tract tracing indicated that entorhinal axons showed delayed growth in reaching the outer molecular layer of the dentate gyrus at postnatal days 2 and 4 in hypothyroid conditions. The proportion of fibers in the outer molecular layer was significantly smaller in the hypothyroid group than in the euthyroid group at postnatal day 4. At postnatal day 10, the pathway showed a layer-specific distribution in the outer molecular layer, similar to the euthyroid group. However, the projected area of entorhinal axons was smaller in the hypothyroid group than in the euthyroid group. An electrophysiological examination showed that hypothyroidism impaired the long-term potentiation of the perforant and the cornu ammonis 3-cornu ammonis 1 pathways. Many repulsive axon guidance molecules were involved in the formation of the entorhinaldentate gyrus pathway. The hypothyroid group had higher levels of erythropoietin-producing hepatocyte ligand A3 and semaphorin 3A than the euthyroid group.
CONCLUSION
We demonstrated that developmental hypothyroidism might influence the development of the entorhinal-dentate gyrus pathway, contributing to impaired long-term potentiation. These findings improve our understanding of neural mechanisms for memory function.
Topics: Animals; Dentate Gyrus; Entorhinal Cortex; Hippocampus; Hypothyroidism; Rats
PubMed: 35390249
DOI: 10.3803/EnM.2021.1343 -
ELife Aug 2023Heterogeneity plays an important role in diversifying neural responses to support brain function. Adult neurogenesis provides the dentate gyrus with a heterogeneous...
Heterogeneity plays an important role in diversifying neural responses to support brain function. Adult neurogenesis provides the dentate gyrus with a heterogeneous population of granule cells (GCs) that were born and developed their properties at different times. Immature GCs have distinct intrinsic and synaptic properties than mature GCs and are needed for correct encoding and discrimination in spatial tasks. How immature GCs enhance the encoding of information to support these functions is not well understood. Here, we record the responses to fluctuating current injections of GCs of different ages in mouse hippocampal slices to study how they encode stimuli. Immature GCs produce unreliable responses compared to mature GCs, exhibiting imprecise spike timings across repeated stimulation. We use a statistical model to describe the stimulus-response transformation performed by GCs of different ages. We fit this model to the data and obtain parameters that capture GCs' encoding properties. Parameter values from this fit reflect the maturational differences of the population and indicate that immature GCs perform a differential encoding of stimuli. To study how this age heterogeneity influences encoding by a population, we perform stimulus decoding using populations that contain GCs of different ages. We find that, despite their individual unreliability, immature GCs enhance the fidelity of the signal encoded by the population and improve the discrimination of similar time-dependent stimuli. Thus, the observed heterogeneity confers the population with enhanced encoding capabilities.
Topics: Mice; Animals; Dentate Gyrus; Neurons; Hippocampus; Neurogenesis
PubMed: 37584478
DOI: 10.7554/eLife.80250 -
Nature Communications Jan 2020Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning. However, the molecular...
Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning. However, the molecular mechanisms that drive engram stabilization during consolidation and consequently ensure its reactivation by memory recall are not fully understood. In this study we manipulate, during memory consolidation, the levels of the de novo DNA methyltransferase 3a2 (Dnmt3a2) selectively within dentate gyrus neurons activated by fear conditioning. We found that Dnmt3a2 upregulation enhances memory performance in mice and improves the fidelity of reconstitution of the original neuronal ensemble upon memory retrieval. Moreover, similar manipulation in a sparse, non-engram subset of neurons does not bias engram allocation or modulate memory strength. We further show that neuronal Dnmt3a2 overexpression changes the DNA methylation profile of synaptic plasticity-related genes. Our data implicates DNA methylation selectively within neuronal ensembles as a mechanism of stabilizing engrams during consolidation that supports successful memory retrieval.
Topics: Animals; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; Dentate Gyrus; Fear; Learning; Male; Memory; Memory Consolidation; Mice; Mice, Inbred C57BL; Neurons
PubMed: 32005851
DOI: 10.1038/s41467-020-14498-4