CA1 Neurons Research Articles

Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall of stimulus features and categories.

Here, we demonstrate the first successful use of static neural stimulation patterns for specific information content. These static patterns were derived by a model that was applied to a subject's own hippocampal spatiotemporal neural codes for memory. We constructed a new model of processes by which the hippocampus encodes specific memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of targeted content into short-term memory. A memory decoding model (MDM) of hippocampal CA3 and CA1 neural firing was computed which derives a stimulation pattern for CA1 and CA3 neurons to be applied during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. MDM electrical stimulation delivered to the CA1 and CA3 locations in the hippocampus during the sample phase of DMS trials facilitated memory of images from the DMS task during a delayed recognition (DR) task that also included control images that were not from the DMS task. Across all subjects, the stimulated trials exhibited significant changes in performance in 22.4% of patient and category combinations. Changes in performance were a combination of both increased memory performance and decreased memory performance, with increases in performance occurring at almost 2 to 1 relative to decreases in performance. Across patients with impaired memory that received bilateral stimulation, significant changes in over 37.9% of patient and category combinations was seen with the changes in memory performance show a ratio of increased to decreased performance of over 4 to 1. Modification of memory performance was dependent on whether memory function was intact or impaired, and if stimulation was applied bilaterally or unilaterally, with nearly all increase in performance seen in subjects with impaired memory receiving bilateral stimulation. These results demonstrate that memory encoding in patients with impaired memory function can be facilitated for specific memory content, which offers a stimulation method for a future implantable neural prosthetic to improve human memory.

Remote Ischemia Postconditioning Mitigates Hippocampal Neuron Impairment by Modulating Cav1.2-CaMKIIα-Aromatase Signaling After Global Cerebral Ischemia in Ovariectomized Rats

Brain-derived estrogen (BDE2) is gaining attention as an endogenous neurotransmitter. Recent research has revealed that selectively removing the aromatase gene, the pivotal enzyme responsible for BDE2 synthesis, in forebrain neurons or astrocytes can lead to synaptic loss and cognitive impairment. It is worth noting that remote ischemia post-conditioning (RIP), a non-invasive technique, has been shown to activate natural protective mechanisms against severe ischemic events. The aim of our study was to investigate whether RIP triggers aromatase-BDE2 signaling, shedding light on its neuroprotective mechanisms after global cerebral ischemia (GCI) in ovariectomized rats. Our findings are as follows: (1) RIP was effective in mitigating ischemic damage in hippocampal CA1 neurons and improved cognitive function after GCI. This was partially due to increased Aro-BDE2 signaling in CA1 neurons. (2) RIP intervention efficiently enhanced pro-survival kinase pathways, such as AKT, ERK1/2, CREB, and suppressed CaMKIIα signaling in CA1 astrocytes induced by GCI. Remarkably, inhibiting CaMKIIα activity led to elevated Aro-BDE2 levels and replicated the benefits of RIP. (3) We also identified the positive mediation of Cav1.2, an LVGCC calcium channel, on CaMKIIα-Aro/BDE2 pathway response to RIP intervention. (4) Significantly, either RIP or CaMKIIα inhibition was found to alleviate reactive astrogliosis, which was accompanied by increased pro-survival A2-astrocyte protein S100A10 and decreased pro-death A1-astrocyte marker C3 levels. In summary, our study provides compelling evidence that Aro-BDE2 signaling is a critical target for the reparative effects of RIP following ischemic insult. This effect may be mediated through the CaV1.2-CaMKIIα signaling pathway, in collaboration with astrocyte-neuron interactions, thereby maintaining calcium homeostasis in the neuronal microenvironment and reducing neuronal damage after ischemia.

MDGA2 Constrains Glutamatergic Inputs Selectively onto CA1 Pyramidal Neurons to Optimize Neural Circuits for Plasticity, Memory, and Social Behavior.

Synapse organizers are essential for the development, transmission, and plasticity of synapses. Acting as rare synapse suppressors, the MAM domain containing glycosylphosphatidylinositol anchor (MDGA) proteins contributes to synapse organization by inhibiting the formation of the synaptogenic neuroligin-neurexin complex. A previous analysis of MDGA2 mice lacking a single copy of Mdga2 revealed upregulated glutamatergic synapses and behaviors consistent with autism. However, MDGA2 is expressed in diverse cell types and is localized to both excitatory and inhibitory synapses. Differentiating the network versus cell-specific effects of MDGA2 loss-of-function requires a cell-type and brain region-selective strategy. To address this, we generated mice harboring a conditional knockout of Mdga2 restricted to CA1 pyramidal neurons. Here we report that MDGA2 suppresses the density and function of excitatory synapses selectively on pyramidal neurons in the mature hippocampus. Conditional deletion of Mdga2 in CA1 pyramidal neurons of adult mice upregulated miniature and spontaneous excitatory postsynaptic potentials, vesicular glutamate transporter 1 intensity, and neuronal excitability. These effects were limited to glutamatergic synapses as no changes were detected in miniature and spontaneous inhibitory postsynaptic potential properties or vesicular GABA transporter intensity. Functionally, evoked basal synaptic transmission and AMPAR receptor currents were enhanced at glutamatergic inputs. At a behavioral level, memory appeared to be compromised in Mdga2 cKO mice as both novel object recognition and contextual fear conditioning performance were impaired, consistent with deficits in long-term potentiation in the CA3-CA1 pathway. Social affiliation, a behavioral analog of social deficits in autism, was similarly compromised. These results demonstrate that MDGA2 confines the properties of excitatory synapses to CA1 neurons in mature hippocampal circuits, thereby optimizing this network for plasticity, cognition, and social behaviors.

Autophagy inhibitors 3-MA and BAF may attenuate hippocampal neuronal necroptosis after global cerebral ischemia-reperfusion injury in male rats by inhibiting the interaction of the RIP3/AIF/CypA complex.

Our previous study found that receptor interacting protein 3 (RIP3) and apoptosis-inducing factor (AIF) were involved in neuronal programmed necrosis during global cerebral ischemia-reperfusion (I/R) injury. Here, we further studied its downstream mechanisms and the role of the autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin A1 (BAF). A 20-min global cerebral I/R injury model was constructed using the 4-vessel occlusion (4-VO) method in male rats. 3-MA and BAF were injected into the lateral ventricle 1 h before ischemia. Spatial and activation changes of proteins were detected by immunofluorescence (IF), and protein interaction was determined by immunoprecipitation (IP). The phosphorylation of H2AX (γ-H2AX) and activation of mixed lineage kinase domain-like protein (p-MLKL) occurred as early as 6 h after reperfusion. RIP3, AIF, and cyclophilin A (CypA) in the neurons after I/R injury were spatially overlapped around and within the nucleus and combined with each other after reperfusion. The survival rate of CA1 neurons in the 3-MA and BAF groups was significantly higher than that in the I/R group. Autophagy was activated significantly after I/R injury, which was partially inhibited by 3-MA and BAF. Pretreatment with both 3-MA and BAF almost completely inhibited nuclear translocation, spatial overlap, and combination of RIP3, AIF, and CypA proteins. These findings suggest that after global cerebral I/R injury, RIP3, AIF, and CypA translocated into the nuclei and formed the DNA degradation complex RIP3/AIF/CypA in hippocampal CA1 neurons. Pretreatment with autophagy inhibitors could reduce neuronal necroptosis by preventing the formation of the RIP3/AIF/CypA complex and its nuclear translocation.

Sequential activity of CA1 hippocampal cells constitutes a temporal memory map for associative learning in mice

Sequential neural dynamics encoded by time cells play a crucial role in hippocampal function. However, the role of hippocampal sequential neural dynamics in associative learning is an open question. We used two-photon Ca2+ imaging of dorsal CA1 (dCA1) neurons in the stratum pyramidale (SP) in head-fixed mice performing a go-no go associative learning task to investigate how odor valence is temporally encoded in this area of the brain. We found that SP cells responded differentially to the rewarded or unrewarded odor. The stimuli were decoded accurately from the activity of the neuronal ensemble, and accuracy increased substantially as the animal learned to differentiate the stimuli. Decoding the stimulus from individual SP cells responding differentially revealed that decision-making took place at discrete times after stimulus presentation. Lick prediction decoded from the ensemble activity of cells in dCA1 correlated linearly with lick behavior. Our findings indicate that sequential activity of SP cells in dCA1 constitutes a temporal memory map used for decision-making in associative learning. VIDEO ABSTRACT.

Electrophysiological Phenotypes of Hippocampal Synaptic and Network Functions in Cannabinoid Receptor 2 Knockout Mice.

Background: The cannabinoid receptor 2 (CB2R), a cannabinoid receptor primarily expressed in immune cells, has been found in the brain, particularly in the hippocampus, where it plays crucial roles in modulating various neural functions, including synaptic plasticity, neuroprotection, neurogenesis, anxiety and stress responses, and neuroinflammation. Despite this growing understanding, the intricate electrophysiological characteristics of hippocampal neurons in CB2R knockout (CB2R KO) mice remain elusive. Aim and Methods: This study aimed to comprehensively assess the electrophysiological traits of hippocampal synaptic and network functions in CB2R KO mice. The focus was on aspects such as synaptic transmission, short- and long-term synaptic plasticity, and neural network synchrony (theta oscillations). Results: Our findings unveiled multiple functional traits in these CB2R KO mice, notably elevated synaptic transmission in hippocampal CA1 neurons, decreased both synaptic short-term plasticity (paired-pulse facilitation) and long-term potentiation (LTP), and impaired neural network synchronization. Conclusion: In essence, this study yields insightful revelations about the influence of CB2Rs on hippocampal neural functions. By illuminating the electrophysiological modifications in CB2R KO mice, our research enriches the comprehension of CB2R involvement in hippocampal function. Such insights could hold implications for advancing our understanding of the neural mechanisms under the influence of CB2Rs within the brain.

Adenosine kinase gene modified mesenchymal stem cell transplantation retards seizure severity and associated cognitive impairment in a temporal lobe epilepsy rat model

PurposeTemporal lobe epilepsy (TLE) has a high risk of developing drug resistant and cognitive comorbidities. Adenosine has potential anticonvulsant effects as an inhibitory neurotransmitter, but drugs targeting its receptors and metabolic enzyme has inevitable side effects. Therefore, we investigated adenosine augmentation therapy for seizure control and cognitive comorbidities in TLE animals. MethodsUsing lentiviral vectors coexpressing miRNA inhibiting the expression of adenosine kinase (ADK), we produced ADK--rMSC (ADK knockdown rat mesenchymal stem cell). ADK--rMSC and LV-con-rMSC (rMSC transduced by randomized scrambled control sequence) were transplanted into the hippocampus of TLE rat respectively. ADK-+DPCPX group was transplanted with ADK--rMSC and intraperitoneally injected with DPCPX (adenosine A1 receptor antagonist). Seizure behavior, EEG, CA1 pyramidal neuron apoptosis, and behavior in Morris water maze and novel object recognition test were studied ResultsAdenosine concentration in the supernatants of 105 ADK--rMSCs was 13.8 ng/ml but not detectable in LV-con-rMSCs. ADK--rMSC (n = 11) transplantation decreased spontaneous recurrent seizure (SRS) duration compared to LV-con-rMSC (n = 11, P < 0.05). CA1 neuron apoptosis was decreased in ADK--rMSC (n = 3, P < 0.05). ADK--rMSC (n = 11) improved the Morris water maze performance of TLE rats compared to LV-con-rMSC (n = 11, escape latency, P < 0.01; entries in target quadrant, P < 0.05). The effect of ADK--rMSC on neuron apoptosis and spatial memory were counteracted by DPCPX. However, ADK--rMSC didn’t improve the performance in novel object recognition test. ConclusionAdenosine augmentation-based ADK--rMSC transplantation is a promising therapeutic candidate for TLE and related cognitive comorbidities.

Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions.

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

Neuronal Hyperactivity in the Hippocampus during the Early Stage of Streptozotocin-Induced Type 1 Diabetes in Mice

Introduction: Cognitive dysfunction due to reduced neuronal transmission in the brain is a major emerging complication in diabetes. However, recent neuroimaging studies have demonstrated non-linear changes including hyperactivity in the hippocampus during the early stage of diabetes. This study aimed to determine the changes in neuronal activity at a single-cell level in hippocampal CA1 pyramidal neurons in the early stage of streptozotocin-induced type 1 diabetes in mice. Methods: Whole-cell patch-clamp recordings from acute brain slices were performed in mice over 4 consecutive weeks following the induction of hyperglycaemia using streptozotocin. In addition, microdialysate was collected from CA1 area while the mice were in an arousal state. The concentrations of glutamate and GABA in the microdialysate were then measured using ultra-performance liquid chromatography with mass spectrometry. Results: CA1 neurons in streptozotocin-induced diabetic mice exhibited higher membrane potentials (p = 0.0052), higher frequency of action potentials (p = 0.0052), and higher frequency of spontaneous excitatory post-synaptic currents (p = 0.037) compared with controls during the second week after hyperglycaemia was established. No changes in electrophysiological parameters were observed during the first, the third, and the fourth week. Moreover, the diabetic mice had higher extracellular glutamate concentration in CA1 area compared with controls (p = 0.021) during the second week after the initiation of diabetes. No change in the extracellular GABA concentration was observed. Conclusion: Our study demonstrated a temporary state of neuronal hyperactivity at the single-cell level in the hippocampal CA1 region during the early stage of diabetes. This neuronal hyperactivity might be related to altered glutamate metabolism and provide clues for future brain-target intervention.

Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development

Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer's disease. Trem2 is essential for microglia-mediated synaptic refinement, but whether Trem2 contributes to shaping neuronal development remains unclear. Here, we demonstrate that Trem2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in the hippocampal cornus ammonis (CA)1 but not in CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled by the transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation, and mitochondrial gene signatures, accompanied by a delay in the maturation of CA1 neurons. Our results unveil a role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.

Reversing Aging: Decline in Complex Olfactory Learning Can be Rectified by Restoring Intrinsic Plasticity of Hippocampal CA1 Pyramidal Neurons.

The acquisition of complex rules requires modifications in intrinsic plasticity of excitatory neurons within relevant brain areas. Olfactory discrimination (OD) rule learning occludes slow calcium-dependent potassium current (sIAHP ) in piriform cortex (PC) pyramidal neurons, which increases their intrinsic neuronal excitability. Similar learning-induced sIAHP changes are demonstrated in hippocampal CA1. The shutdown of sIAHP is mediated by the metabotropic activation of the kainate subtype glutamatergic receptor, GluK2. Here, the duration of training required for OD rule learning increased significantly as the mice matured and aged is first shown, which appears earlier in 5xFAD mice. At the cellular biophysical level, aging is accompanied by reduction in the post-burst AHP in these neurons, while neuronal excitability remains stable. This is in contrast to aging CA1 neurons that exhibit enhanced post-burst AHPs in previous reports. Kainate reduces post-burst AHP in adults, but not in aged PC neurons, whereas it reduces post-burst AHPs in hippocampal CA1 pyramidal neurons of both young and aged mice. Overexpression of GluK2 in CA1 neurons restores OD learning capabilities in aged wild-type and 5xFAD mice, to a level comparable to young adults. Activation of GluK2 receptors in selectively vulnerable neurons can prevent aging-related cognitive decline is suggested.

Knockout of NMDARs in CA1 and dentate gyrus fails to impair temporal control of conditioned behavior in mice.

The hippocampus has been implicated in temporal learning. Plasticity within the hippocampus requires NMDA receptor-dependent glutamatergic neurotransmission. We tested the prediction that hippocampal NMDA receptors are required for learning about time by testing mice that lack postembryonal NMDARs in the CA1 and dentate gyrus (DG) hippocampal subfields on three different appetitive temporal learning procedures. The conditional knockout mice (Grin1ΔDCA1 ) showed normal sensitivity to cue duration, responding at a higher level to a short duration cue than compared to a long duration cue. Knockout mice also showed normal precision and accuracy of response timing in the peak procedure in which reinforcement occurred after 10 s delay within a 30 s cue presentation. Mice were tested on the matching of response rates to reinforcement rates on instrumental conditioning with two levers reinforced on a concurrent variable interval schedule. Pressing on one lever was reinforced at a higher rate than the other lever. Grin1ΔDGCA1 mice showed normal sensitivity to the relative reinforcement rates of the levers. In contrast to the lack of effect of hippocampal NMDAR deletion on measures of temporal sensitivity, Grin1ΔDGCA1 mice showed increased baseline measures of magazine activity and lever pressing. Furthermore, reversal learning was enhanced when the reward contingencies were switched in the lever pressing task, but this was true only for mice trained with a large difference between relative reinforcement rates between the levers. The results failed to demonstrate a role for NMDARs in excitatory CA1 and DG neurons in learning about temporal information.

Voluntary exercise during puberty promotes spatial memory and hippocampal DG/CA3 synaptic transmission in mice.

Physical exercise has been shown to have an impact on memory and hippocampal function across different age groups. Nevertheless, the influence and mechanisms underlying how voluntary exercise during puberty affects memory are still inadequately comprehended. This research aims to examine the impacts of self-initiated physical activity throughout adolescence on spatial memory. Developing mice were exposed to a 4-wk voluntary wheel running exercise protocol, commencing at the age of 30d. After engaging in voluntary wheel running exercise during development, there was an enhancement in spatial memory. Moreover, hippocampal dentate gyrus and CA3 neurons rather than CA1 neurons exhibited an increase in the miniature excitatory postsynaptic currents and miniature inhibitory postsynaptic currents. In addition, there was an increase in the expression of NR2A/NR2B subunits of N-methyl-D-aspartate receptors and α1GABAA subunit of gamma-aminobutyric acid type A receptors, as well as dendritic spine density, specifically within dentate gyrus and CA3 regions rather than CA1 region. The findings suggest that voluntary exercise during development can enhance spatial memory in mice by increasing synapse numbers and improving synaptic transmission in hippocampal dentate gyrus and CA3 regions, but not in CA1 region. This study sheds light on the neural mechanisms underlying how early-life exercise improves cognitive function.

Mimicking hypomethylation of FUS requires liquid–liquid phase separation to induce synaptic dysfunctions

The hypomethylation of fused in sarcoma (FUS) in frontotemporal lobar degeneration promotes the formation of irreversible condensates of FUS. However, the mechanisms by which these hypomethylated FUS condensates cause neuronal dysfunction are unknown. Here we report that expression of FUS constructs mimicking hypomethylated FUS causes aberrant dendritic FUS condensates in CA1 neurons. These hypomethylated FUS condensates exhibit spontaneous, and activity induced movement within the dendrite. They impair excitatory synaptic transmission, postsynaptic density-95 expression, and dendritic spine plasticity. These neurophysiological defects are dependent upon both the dendritic localisation of the condensates, and their ability to undergo liquid–liquid phase separation. These results indicate that the irreversible liquid–liquid phase separation is a key component of hypomethylated FUS pathophysiology in sporadic FTLD, and this can cause synapse dysfunction in sporadic FTLD.

Automated analysis of animal behavior and its relation to key aspects of the environment reveals new cognitive specializations of neurons

A thorough analysis of animal behavior is essential for examining the relationship between specific neuron activations with the elements of the external environment, behavior, or internal state. Machine learning techniques have made some advancements in automatic segmentation of animal behavior based on data concerning the location of animal body parts [1–3]. At present, these methods cannot achieve the level of segmentation accuracy desired or make correlations between an animal’s behavioral acts and key environmental factors. To address this issue, the authors have created a software package that can extract a variety of behavioral variables from video recordings of animals in experimental settings, enabling mathematical analysis of a behavioral act continuum. The identification of specific aspects of an animal’s anatomy is crucial for extracting a vast array of behavioral variables. In order to accomplish this task, our team employed DeepLabCut, an accessible toolkit for tracking experimental animal behavior that operates on the principle of transfer learning through deep neural networks. We have devised a technique to ascertain the positions of animal body parts in diverse behavioral situations, resulting in a body parts collection meeting two criteria: offering superior responsiveness to small motor movements of the animal and delivering a high percentage of correct body part locations. In scenarios employing camera shooting from above, such a collection encompasses the nose, ears, tail base, body center, forelimbs, hind limbs, and both flanks of the animal’s body. Next, we created software tools to extract and annotate behavioral variables from data on animal kinematics in various cognitive tasks. Our automated system comprises two main scripting modules: CreatePreset and BehaviorAnalyzer. The CreatePreset module interacts with users to select the type of arena geometry, object location, and necessary temporal and spatial parameters for analysis. The script’s result saves as a mat-file for analyzing the behavior of all experiment videos, assuming a constant relative position of the arena and the video camera alongside the experiment’s design. The BehaviorAnalyzer module conducts initial processing on time series data consisting of coordinates of an animal’s body parts. This results in the formation of a kinematogram, which details the kinematics of the body parts. The module then isolates individual behavioral acts of the animal and annotates its behavior based on motivational and environmental factors. Using mutual information-based methods, we analyzed the specialization of hippocampal CA1 neurons in animals as they explored arenas with varying degrees of novelty. Through the analysis, we have identified neurons that exhibit selectivity in relation to specific continuous kinematic parameters governing the posture and trajectory of the animal. These parameters include the animal’s location in the arena space (X and Y coordinates), as well as the speed and angle of rotation of the animal’s head (i.e. absolute orientation in the arena). Neurons specialized in discrete acts of behavior were identified, including rests, locomotions, freezing, rears, and acts of interaction with objects. Furthermore, a selective activation of neurons was found with regard to an additional set of distinct parameters, which combine the animal’s location in the arena and its speed.

Calcium activity of hippocampal CA1 neurons during memory formation and retrieval in young and old mice

Calcium activity of hippocampal CA1 neurons during memory formation and retrieval in young and old mice

A bridge to recovery: Acute amantadine prior to environmental enrichment after brain trauma augments cognitive benefit

Environmental enrichment (EE) facilitates motor and cognitive recovery after traumatic brain injury (TBI). Historically, EE has been provided immediately and continuously after TBI, but this paradigm does not model the clinic where rehabilitation is typically not initiated until after critical care. Yet, treating TBI early may facilitate recovery. Hence, we sought to provide amantadine (AMT) as a bridge therapy before commencing EE. It was hypothesized that bridging EE with AMT would augment motor and cognitive benefits. Anesthetized adult male rats received a cortical impact (2.8 mm deformation at 4 m/s) or sham surgery and then were housed in standard (STD) conditions where they received intraperitoneal AMT (10 mg/kg or 20 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24 h after surgery and once daily during the 6-day bridge phase or once daily for 19 days for the non-bridge groups (i.e., continuously STD-housed) to compare the effects of acute AMT plus EE vs. chronic AMT alone. Abbreviated EE, which was presented to closer emulate clinical rehabilitation (e.g., 6 h/day), began on day 7 for the AMT bridge and chronic EE groups. Motor (beam-walking) and cognition (acquisition of spatial learning and memory) were assessed on days 7–11 and 14–19, respectively. Cortical lesion volume and hippocampal cell survival were quantified on day 21. EE, whether provided in combination with VEH or AMT, and AMT (20 mg/kg) + STD, benefitted motor and cognition vs. the STD-housed VEH and AMT (10 mg/kg) groups (p < 0.05). The AMT (20 mg/kg) + EE group performed better than the VEH + EE, AMT (10 mg/kg) + EE, and AMT (20 mg/kg) + STD groups in the acquisition of spatial learning (p < 0.05) but did not differ in motor function (p > 0.05). All groups receiving EE exhibited decreased cortical lesion volumes and increased CA3 neuron survival relative to the STD-housed groups (p < 0.05) but did not differ from one another (p > 0.05). The added cognitive benefit achieved by bridging EE with AMT (20 mg/kg) supports the hypothesis that the temporal separation of combinational therapies is more effective after TBI.

Analysis of hippocampus in rats with acute brain ischemia-reperfusion injury treated with leuprolide acetate, an agonist of GnRH.

The hippocampus is highly vulnerable to damage in the brain ischemia-reperfusion injury model. Leuprolide acetate has been shown to promote neurological recovery after injury in various regions of the central nervous system. The objective of this study was to assess the histology of the hippocampus and the expression of neuronal recovery markers, specifically the 200 kDa neurofilaments and the myelin basic protein, in rats with brain ischemia-reperfusion injury treated with leuprolide acetate. The rats were divided into three groups: Sham, ischemia-reperfusion with saline solution, and ischemia-reperfusion treated with leuprolide acetate. Coronal brain slices were obtained and stained with hematoxylin-eosin. The histological analysis involved quantifying the number of neurons in the hippocampal regions CA1, CA3 and DG. The myelin basic protein and neurofilaments were quantified using western blot. The number of neurons in CA1 and DG was significantly higher in the leuprolide acetate group compared to the untreated group. Additionally, the expression of neurofilament and myelin basic protein markers was significantly increased in rats treated with leuprolide acetate compared to the untreated rats. Leuprolide acetate promotes the recovery of hippocampal neurons in an acute brain ischemia-reperfusion injury model. These findings suggest that leuprolide acetate could be a potential therapeutic intervention for reversing damage in hippocampal ischemic lesions.

Visuotactile integration facilitates mirror-induced self-directed behavior through activation of hippocampal neuronal ensembles in mice

Remembering the visual features of oneself is critical for self-recognition. However, the neural mechanisms of how the visual self-image is developed remain unknown because of the limited availability of behavioral paradigms in experimental animals. Here, we demonstrate a mirror-induced self-directed behavior (MSB) in mice, resembling visual self-recognition. Mice displayed increased mark-directed grooming to remove ink placed on their heads when an ink-induced visual-tactile stimulus contingency occurred. MSB required mirror habituation and social experience. The chemogenetic inhibition of dorsal or ventral hippocampal CA1 (vCA1) neurons attenuated MSB. Especially, a subset of vCA1 neurons activated during the mirror exposure was significantly reactivated during re-exposure to the mirror and was necessary for MSB. The self-responding vCA1 neurons were also reactivated when mice were exposed to a conspecific of the same strain. These results suggest that visual self-image may be developed through social experience and mirror habituation and stored in a subset of vCA1 neurons.

JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer’s disease

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer’s disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.