Dissociations in perceptual discrimination following selective damage to the dentate gyrus versus CA1 subfield of the hippocampus.

The hippocampus (HPC) is well-known for its involvement in declarative (consciously accessible) memory, but there is evidence that it may also play a role in complex perceptual discrimination. Separate research has demonstrated separable contributions of HPC subregions to component memory processes, with the dentate gyrus (DG) required for mnemonic discrimination of similar inputs and the CA1 subfield required for retention and retrieval, but contributions of these subregions to perceptual processes is understudied. The current study examined the nature and extent of a double dissociation between the dentate gyrus (DG) to discrimination processes and CA1 subfield to retention/retrieval by testing two unique individuals with bilateral damage to the DG (case BL) and CA1 (case BR). We tested BL and BR on a wide range of standardized neuropsychological tests to assess information encoding and retention/retrieval and co-opted many measures to assess perceptual discrimination. Compared to normative data, BL exhibited performance below expectations on most measures requiring perceptual discrimination and on measures of encoding but demonstrated intact retention. Conversely, BR showed no difficulties with perceptual discrimination or verbal encoding but exhibited poor verbal retention, as well as poor encoding and retention of spatial/integrative tasks (e.g., object in a location). These results indicate that, despite its prominent role in memory, the DG is necessary for perceptual discrimination and encoding, whereas CA1 is necessary for retention/retrieval and encoding of spatial information. The pattern of results highlights the critical nature of individual case studies in the nuanced understanding of HPC subfield contributions to different memory processes, as well as the utility of repurposing neuropsychological measures to capture individual differences.

Hippocampal neurodegeneration induces transient endogenous regeneration and long-term exhaustion of the neurogenic niche.

The hippocampal dentate gyrus, responds to diverse pathological stimuli through neurogenesis. This phenomenon, observed following brain injury or neurodegeneration, is postulated to contribute to neuronal repair and functional recovery, thereby presenting an avenue for endogenous neuronal restoration. This study investigated the extent of regenerative response in hippocampal neurogenesis by leveraging the well-established kainic acid-induced status epilepticus model in vivo. In our study, we observed the activation and proliferation of neuronal progenitors or neural stem cell (NSC) and their subsequent migration to the injury sites following the seizure. At the injury sites, new neurons (Tuj1+BrdU+ and NeuN+BrdU+) have been generated indicating regenerative and reparative roles of the progenitor cells. We further detected whether this transient neurogenic burst, which might be a response towards an attempt to repair the brain, is associated with persistent long-term exhaustion of the dentate progenitor cells and impairment of adult neurogenesis marked by downregulation of Ki67, HoPX, and Sox2 with BrdU+ cell in the later part of life. Our studies suggest that the adult brain has the constitutive endogenous regenerative potential for brain repair to restore the damaged neurons, meanwhile, in the long term, it accelerates the depletion of the finite NSC pool in the hippocampal neurogenic niche by changing its proliferative and neurogenic capacity. A thorough understanding of the impact of modulating adult neurogenesis will eventually be required to design novel therapeutics to stimulate or assist brain repair while simultaneously preventing the adverse effects of early robust neurogenesis on the proliferative potential of endogenous neuronal progenitors.

Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions.

Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, is unknown. Here, we determined the effects of ELS-induced by limited bedding and nesting material during the first week of life (postnatal days [P]2-9) on microglial (i) morphology; (ii) hippocampal gene expression; and (iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice. The hippocampus of ELS-exposed adult mice displayed altered proportions of morphological subtypes of microglia, as well as microglial transcriptomic changes related to the tumor necrosis factor response and protein ubiquitination. ELS exposure leads to distinct gene expression profiles during microglial development from P9 to P200 and in response to an LPS challenge at P200. Functionally, synaptosomes from ELS-exposed mice were phagocytosed less by age-matched microglia. At P200, but not P9, ELS microglia showed reduced synaptosome phagocytic capacity when compared to control microglia. Lastly, we confirmed the ELS-induced increased expression of the phagocytosis-related gene GAS6 that we observed in mice, in the dentate gyrus of individuals with a history of child abuse using in situ hybridization. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.

Nitric oxide impairs spatial learning and memory in a rat model of Alzheimer's disease via disturbance of glutamate response in the hippocampal dentate gyrus during spatial learning.

Nitric oxide (NO)-dependent pathways may play a significant role in the decline of synaptic and cognitive functions in Alzheimer's disease (AD). However, whether NO in the hippocampal dentate gyrus (DG) is involved in the spatial learning and memory impairments of AD by affecting the glutamate (Glu) response during these processes is not well-understood. Here, we prepared an AD rat model by long-term i.p. of D-galactose into ovariectomized rats, and then the effects of L-NMMA (a NO synthase inhibitor) on Glu concentration and amplitude of field excitatory postsynaptic potential (fEPSP) were measured in the DG region during the Morris water maze (MWM) test in freely-moving rats. During the MWM test, compared with the sham group, the escape latency was increased in the place navigation trial, and the percentage of time spent in target quadrant and the number of platform crossings were decreased in the spatial probe trial, in addition, the increase of fEPSP amplitude in the DG was significantly attenuated in AD group rats. L-NMMA significantly attenuated the spatial learning and memory impairment in AD rats, and reversed the inhibitory effect of AD on increase of fEPSP amplitude in the DG during the MWM test. In sham group rats, the Glu level in the DG increased significantly during the MWM test, and this response was markedly enhanced in AD rats. Furthermore, the response of Glu in the DG during spatial learning was recovered by microinjection of L-NMMA into the DG. Our results suggest that NO in the DG impairs spatial learning and memory and related synaptic plasticity in AD rats, by disturbing the Glu response during spatial learning.

Scavenging Tumor Necrosis Factor α Does Not Affect Inhibition of Dentate Granule Cells Following In Vitro Entorhinal Cortex Lesion.

Neurons that lose part of their afferent input remodel their synaptic connections. While cellular and molecular mechanisms of denervation-induced changes in excitatory neurotransmission have been identified, little is known about the signaling pathways that control inhibition in denervated networks. In this study, we used mouse entorhino-hippocampal tissue cultures of both sexes to study the role of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) in denervation-induced plasticity of inhibitory neurotransmission. In line with our previous findings in vitro, an entorhinal cortex lesion triggered a compensatory increase in the excitatory synaptic strength of partially denervated dentate granule cells. Inhibitory synaptic strength was not changed 3 days after the lesion. These functional changes were accompanied by a recruitment of microglia in the denervated hippocampus, and experiments in tissue cultures prepared from TNF-reporter mice [C57BL/6-Tg(TNFa-eGFP)] showed increased TNFα expression in the denervated zone. However, inhibitory neurotransmission was not affected by scavenging TNFα with a soluble TNF receptor. In turn, a decrease in inhibition, i.e., decreased frequencies of miniature inhibitory postsynaptic currents, was observed in denervated dentate granule cells of microglia-depleted tissue cultures. We conclude from these results that activated microglia maintain the inhibition of denervated dentate granule cells and that TNFα is not required for the maintenance of inhibition after denervation.

Impact of neurodegenerative diseases on human adult hippocampal neurogenesis.

Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the contribution of adult hippocampal neurogenesis (AHN) to amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, and frontotemporal dementia, we studied postmortem human samples. We found that adult-born dentate granule cells showed abnormal morphological development and changes in the expression of differentiation markers. The ratio of quiescent to proliferating hippocampal neural stem cells shifted, and the homeostasis of the neurogenic niche was altered. Aging and neurodegenerative diseases reduced the phagocytic capacity of microglia, triggered astrogliosis, and altered the microvasculature of the dentate gyrus. Thus, enhanced vulnerability of AHN to neurodegeneration might underlie hippocampal dysfunction during physiological and pathological aging in humans.

Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy.

In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is because of a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation, and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy.SIGNIFICANCE STATEMENT People with temporal lobe epilepsy (TLE) often have learning and memory impairments, sometimes occurring earlier than the first seizure, but those symptoms and their biological underpinnings are poorly understood. We focused on the dentate gyrus, a brain region that is critical to avoid confusion between similar memories and is anatomically disorganized in TLE. We show that both humans and mice with TLE experience confusion between similar situations. This impairment coincides with a failure of the dentate gyrus to disambiguate similar input signals because of pathologic bursting in a subset of neurons. Our work bridges seizure-oriented and memory-oriented views of the dentate gyrus function, suggests a mechanism for cognitive symptoms in TLE, and supports a long-standing hypothesis of episodic memory theories.

Preventive effect of Ninjin-yoei-to, a Kampo medicine, on amyloid ß1-42-induced neurodegeneration via intracellular Zn2+ toxicity in the dentate gyrus.

Ninjin-yoei-to (NYT), a Kampo medicine, has ameliorative effects on cognitive dysfunction via enhancing cholinergic neuron activity. To explore an efficacy of NYT administration for prevention and cure of Alzheimer's disease, here we examined the effect of NYT on amyloid ß1-42 (Aß1-42)-induced neurodegeneration in the dentate gyrus. A diet containing 3% NYT was administered to mice for 2 weeks and human Aß1-42 was intracerebroventricularly injected. Neurodegeneration in the dentate granule cell layer of the hippocampus, which was determined 2 weeks after the injection, was rescued by administration of the diet for 4 weeks. Aß staining (uptake) was not modified in the dentate granule cell layer by pre-administration of the diet for 2 weeks, while Aß1-42-induced increase in intracellular Zn2+ was reduced, suggesting that pre-administration of NYT prior to Aß injection is effective for reducing Aß1-42-induced Zn2+ toxicity in the dentate gyrus. As a matter of fact, Aß1-42-induced neurodegeneration in the dentate gyrus was rescued by pre-administration of NYT. Interestingly, the level of metallothioneins, intracellular Zn2+-binding proteins, which can capture Zn2+ from Zn-Aß1-42 complexes, was elevated in the dentate granule cell layer by pre-administration of NYT. The present study suggests that pre-administration of NYT prevents Aß1-42-mediated neurodegeneration in the dentate gyurs by induced synthesis of metallothioneins, which reduces intracellular Zn2+ toxicity induced by Aß1-42.

Maximally selective single-cell target for circuit control in epilepsy models.

Neurological and psychiatric disorders are associated with pathological neural dynamics. The fundamental connectivity patterns of cell-cell communication networks that enable pathological dynamics to emerge remain unknown. Here, we studied epileptic circuits using a newly developed computational pipeline that leveraged single-cell calcium imaging of larval zebrafish and chronically epileptic mice, biologically constrained effective connectivity modeling, and higher-order motif-focused network analysis. We uncovered a novel functional cell type that preferentially emerged in the preseizure state, the superhub, that was unusually richly connected to the rest of the network through feedforward motifs, critically enhancing downstream excitation. Perturbation simulations indicated that disconnecting superhubs was significantly more effective in stabilizing epileptic circuits than disconnecting hub cells that were defined traditionally by connection count. In the dentate gyrus of chronically epileptic mice, superhubs were predominately modeled adult-born granule cells. Collectively, these results predict a new maximally selective and minimally invasive cellular target for seizure control.

The role of dentate gyrus dopaminergic receptors in the lateral hypothalamic-induced antinociception during persistent inflammatory pain in male rats.

The lateral hypothalamus (LH) is one of the key brain areas involved in pain modulation. Also, the dentate gyrus (DG) of the hippocampus expresses various receptors, including dopaminergic receptors. Dopaminergic receptors play a key role in pain transmission and modulation within the brain. The present study aimed to investigate the involvement of DG dopaminergic receptors in the LH-induced antinociception during the presence of inflammatory pain. Male Wistar rats were used in this study. Cannulae were unilaterally implanted in their skull for microinjections into the LH and DG. The LH was chemically stimulated by carbachol injection (250 nM/0.5 µl saline). In separate groups, different doses (0.25, 1, and 4 µg/0.5 µl vehicle) of the D1- and D2-like dopamine receptor antagonists (SCH23390 and Sulpiride, respectively) were microinjected into the DG, 5 min prior to intra-LH injection of carbachol. Five min after the second injection, formalin test as a persistent inflammatory pain model in animals was done in all rats. The results revealed that carbachol could induce antinociception following formalin injection into rat's hind paw. The 4 µg dose of both antagonists significantly reduced the LH stimulation-induced antinociception in both phases of formalin pain responses. Although the 1 µg dose of sulpiride significantly reduced antinociception during both phases, 1 µg SCH23390 could only reduce this antinociception during the late phase. These findings demonstrate the involvement of DG dopaminergic receptors in the LH-induced antinociception. The results also suggest that the effectiveness of DG dopaminergic receptors is more pronounced during the late phase of formalin-induced pain responses.

Hippocampal sub-networks exhibit distinct spatial representation deficits in Alzheimer's disease model mice.

Not much is known about how the dentate gyrus (DG) and hippocampal CA3 networks, critical for memory and spatial processing, malfunction in Alzheimer's disease (AD). While studies of associative memory deficits in AD have focused mainly on behavior, here, we directly measured neurophysiological network dysfunction. We asked what the pattern of deterioration of different networks is during disease progression. We investigated how the associative memory-processing capabilities in different hippocampal subfields are affected by familial AD (fAD) mutations leading to amyloid-ß dyshomeostasis. Specifically, we focused on the DG and CA3, which are known to be involved in pattern completion and separation and are susceptible to pathological alterations in AD. To identify AD-related deficits in neural-ensemble dynamics, we recorded single-unit activity in wild-type (WT) and fAD model mice (APPSwe+PSEN1/ΔE9) in a novel tactile morph task, which utilizes the extremely developed somatosensory modality of mice. As expected from the sub-network regional specialization, we found that tactile changes induced lower rate map correlations in the DG than in CA3 of WT mice. This reflects DG pattern separation and CA3 pattern completion. In contrast, in fAD model mice, we observed pattern separation deficits in the DG and pattern completion deficits in CA3. This demonstration of region-dependent impairments in fAD model mice contributes to understanding of brain networks deterioration during fAD progression. Furthermore, it implies that the deterioration cannot be studied generally throughout the hippocampus but must be researched at a finer resolution of microcircuits. This opens novel systems-level approaches for analyzing AD-related neural network deficits.

Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model.

Background: Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods: To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results: Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-ß and NMDAR2-α subtypes as well as their downstream signaling proteins ß-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of ß-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-ß association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions: These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine's lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.

Impaired pattern separation in Tg2576 mice is associated with hyperexcitable dentate gyrus caused by Kv4.1 downregulation.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes memory loss. Most AD researches have focused on neurodegeneration mechanisms. Considering that neurodegenerative changes are not reversible, understanding early functional changes before neurodegeneration is critical to develop new strategies for early detection and treatment of AD. We found that Tg2576 mice exhibited impaired pattern separation at the early preclinical stage. Based on previous studies suggesting a critical role of dentate gyrus (DG) in pattern separation, we investigated functional changes in DG of Tg2576 mice. We found that granule cells in DG (DG-GCs) in Tg2576 mice showed increased action potential firing in response to long depolarizations and reduced 4-AP sensitive K+-currents compared to DG-GCs in wild-type (WT) mice. Among Kv4 family channels, Kv4.1 mRNA expression in DG was significantly lower in Tg2576 mice. We confirmed that Kv4.1 protein expression was reduced in Tg2576, and this reduction was restored by antioxidant treatment. Hyperexcitable DG and impaired pattern separation in Tg2576 mice were also recovered by antioxidant treatment. These results highlight the hyperexcitability of DG-GCs as a pathophysiologic mechanism underlying early cognitive deficits in AD and Kv4.1 as a new target for AD pathogenesis in relation to increased oxidative stress.

Impaired plasticity of intrinsic excitability in the dentate gyrus alters spike transfer in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline related to deficits in synaptic transmission and plasticity. We report in APP/PS1 mice, a double transgenic mouse model of AD, that females displayed an early burden of Aß plaques load in the stratum moleculare of the dentate gyrus (DG) together with prominent neuroinflammatory activation of astrocytes and microglia. Robust deficits in hippocampus-dependent memory tasks were observed in APP/PS1 female mice as early as 3 months of age. We then studied the functional properties of the lateral perforant path (LPP) to DG granule cells. Remarkably DG granule cells displayed higher intrinsic excitability in APP/PS1 female mice. We showed that the long term potentiation of population spike amplitude induced by high frequency stimulation (HFS) at LPP-DG granule cells synapse is impaired in APP/PS1 female mice. HFS induced plasticity of intrinsic excitability in DG granule cells without inducing noticeable modification of synaptic strength. Furthermore, the enhanced intrinsic excitability was potentiated to a greater extent in APP/PS1 as compared to control mice following HFS. Our study shows that changes in the intrinsic excitability of DG granule cells in AD contribute to the dysfunctional transfer of information from the entorhinal cortex to the hippocampus.

Behavioral profiling reveals an enhancement of dentate gyrus paired pulse inhibition in a rat model of PTSD.

We recently introduced behavioral profiling as a translational approach to increase the validity of animal models of posttraumatic stress disorder (PTSD). Behavioral profiling utilizes the response of a 'normal population' of control animals and compares the performance of animals with a history of traumatic stress in different behavioral tests that can capture PTSD-like symptoms. Thus, affected, PTSD-like individuals can be subdivided from resilient trauma-exposed animals. While in our recent study we focused mainly on tests for activity and anxiety, we now expand the behavioral tests battery and include also fear memory and extinction tasks as well as a spatial object recognition test in our behavioral profiling approach. Utilizing underwater trauma as the traumatic event, we found that only a small subset of animals exposed to underwater trauma showed lasting increases in anxiety-like behavior and heightened emotional memory formation. Adding juvenile stress as a model for childhood adversity increased the prevalence of such affected animals and furthermore and induced additional cognitive deficits in a subgroup of such emotionally affected individuals. In addition, multiple affected individual rats displayed increased local circuit activity in the dorsal dentate gyrus, as measured in vivo with paired pulse protocols in anesthetized animals. Together, our findings highlight behavioral profiling, refined by including multiple behavioral tests, as a valid tool to identify PTSD-like vs. resilient individual animals and further suggest that enhanced local inhibition in specific circuits of the dorsal dentate gyrus may be associated with the observed symptoms.

Contribution of Hypothyroidism to Cognitive Impairment and Hippocampal Synaptic Plasticity Regulation in an Animal Model of Depression.

The role that thyroid hormone deficiency plays in depression and synaptic plasticity in adults has only begun to be elucidated. This paper analyzes the possible link between depression and hypothyroidism in cognitive function alterations, using Wistar-Kyoto (WKY-an animal model of depression) rats and control Wistar rats under standard and thyroid hormone deficiency conditions (propylthiouracil administration-PTU). A weakening of memory processes in the WKY rats is shown behaviorally, and in the reduction of long-term potentiation (LTP) in the dentate gyrus (DG) and CA1 hippocampal regions. PTU administration decreased LTP and increased basal excitatory transmission in the DG in Wistar rats. A decrease in short-term synaptic plasticity is shown by the paired-pulse ratio measurement, occurring during hypothyroidism in DG and CA1 in WKY rats. Differences between the strains may result from decreases in the p-CaMKII, p-AKT, and the level of acetylcholine, while in the case of the co-occurrence of depression and hypothyroidism, an increase in the p-ERK1-MAP seemed to be important. Obtained results show that thyroid hormones are less involved in the inhibition of glutamate release and/or excitability of the postsynaptic neurons in WKY rats, which may indicate a lower sensitivity of the hippocampus to the action of thyroid hormones in depression.

2-Pentadecyl-2-oxazoline ameliorates memory impairment and depression-like behaviour in neuropathic mice: possible role of adrenergic alpha2- and H3 histamine autoreceptors.

Neuropathic pain (NP) remains an untreatable disease due to the complex pathophysiology that involves the whole pain neuraxis including the forebrain. Sensory dysfunctions such as allodynia and hyperalgesia are only part of the symptoms associated with neuropathic pain that extend to memory and affectivity deficits. The development of multi-target molecules might be a promising therapeutic strategy against the symptoms associated with NP. 2-pentadecyl-2-oxazoline (PEA-OXA) is a plant-derived agent, which has shown effectiveness against chronic pain and associated neuropsychiatric disorders. The molecular mechanisms by which PEA-OXA exerts its effects are, however, only partially known. In the current study, we show that PEA-OXA, besides being an alpha2 adrenergic receptor antagonist, also acts as a modulator at histamine H3 receptors, and report data on its effects on sensory, affective and cognitive symptoms associated with the spared nerve injury (SNI) model of neuropathic pain in mice. Treatment for 14 days with PEA-OXA after the onset of the symptoms associated with neuropathic pain resulted in the following effects: (i) allodynia was decreased; (ii) affective/cognitive impairment associated with SNI (depression, spatial, and working memories) was counteracted; (iii) long-term potentiation in vivo in the lateral entorhinal cortex-dentate gyrus (perforant pathway, LPP) was ameliorated, (iv) hippocampal glutamate, GABA, histamine, norepinephrine and dopamine level alterations after peripheral nerve injury were reversed, (v) expression level of the TH positive neurons in the Locus Coeruleus were normalized. Thus, a 16-day treatment with PEA-OXA alleviates the sensory, emotional, cognitive, electrophysiological and neurochemical alterations associated with SNI-induced neuropathic pain.

Long-term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy.

OBJECTIVE: One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons. METHODS: Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction. RESULTS: In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection. SIGNIFICANCE: This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.

Life-long brain compensatory responses to galactic cosmic radiation exposure.

Galactic cosmic radiation (GCR) composed of high-energy, heavy particles (HZE) poses potentially serious hazards to long-duration crewed missions in deep space beyond earth's magnetosphere, including planned missions to Mars. Chronic effects of GCR exposure on brain structure and cognitive function are poorly understood, thereby limiting risk reduction and mitigation strategies to protect against sequelae from exposure during and after deep-space travel. Given the selective vulnerability of the hippocampus to neurotoxic insult and the importance of this brain region to learning and memory, we hypothesized that GCR-relevant HZE exposure may induce long-term alterations in adult hippocampal neurogenesis, synaptic plasticity, and hippocampal-dependent learning and memory. To test this hypothesis, we irradiated 3-month-old male and female mice with a single, whole-body dose of 10, 50, or 100 cGy 56Fe ions (600 MeV, 181 keV/µm) at Brookhaven National Laboratory. Our data reveal complex, dynamic, time-dependent effects of HZE exposure on the hippocampus. Two months post exposure, neurogenesis, synaptic plasticity and learning were impaired compared to sham-irradiated, age-matched controls. By six months post-exposure, deficits in spatial learning were absent in irradiated mice, and synaptic potentiation was enhanced. Enhanced performance in spatial learning and facilitation of synaptic plasticity in irradiated mice persisted 12 months post-exposure, concomitant with a dramatic rebound in adult-born neurons. Synaptic plasticity and spatial learning remained enhanced 20 months post-exposure, indicating a life-long influence on plasticity and cognition from a single exposure to HZE in young adulthood. These findings suggest that GCR-exposure can persistently alter brain health and cognitive function during and after long-duration travel in deep space.

Rapid Aging in the Perforant Path Projections to the Rodent Dentate Gyrus.

Why layers II/III of entorhinal cortex (EC) deteriorate in advance of other regions during the earliest stages of Alzheimer's disease is poorly understood. Failure of retrograde trophic support from synapses to cell bodies is a common cause of neuronal atrophy, and we accordingly tested for early-life deterioration in projections of rodent layer II EC neurons. Using electrophysiology and quantitative imaging, changes in EC terminals during young adulthood were evaluated in male rats and mice. Field excitatory postsynaptic potentials, input/output curves, and frequency following capacity by lateral perforant path (LPP) projections from lateral EC to dentate gyrus were unchanged from 3 to 8-10 months of age. In contrast, the unusual presynaptic form of long-term potentiation (LTP) expressed by the LPP was profoundly impaired by 8 months in rats and mice. This impairment was accompanied by a reduction in the spine to terminal endocannabinoid signaling needed for LPP-LTP induction and was offset by an agent that enhances signaling. There was a pronounced age-related increase in synaptophysin within LPP terminals, an effect suggestive of incipient pathology. Relatedly, presynaptic levels of TrkB-receptors mediating retrograde trophic signaling-were reduced in the LPP terminal field. LTP and TrkB content were also reduced in the medial perforant path of 8- to 10-month-old rats. As predicted, performance on an LPP-dependent episodic memory task declined by late adulthood. We propose that memory-related synaptic plasticity in EC projections is unusually sensitive to aging, which predisposes EC neurons to pathogenesis later in life.SIGNIFICANCE STATEMENT Neurons within human superficial entorhinal cortex are particularly vulnerable to effects of aging and Alzheimer's disease, although why this is the case is not understood. Here we report that perforant path projections from layer II entorhinal cortex to the dentate gyrus exhibit rapid aging in rodents, including reduced synaptic plasticity and abnormal protein content by 8-10 months of age. Moreover, there was a substantial decline in the performance of an episodic memory task that depends on entorhinal cortical projections at the same ages. Overall, the results suggest that the loss of plasticity and related trophic signaling predispose the entorhinal neurons to functional decline in relatively young adulthood.