Deficits In Rodent Models Research Articles

RADT-10. LITHIUM TREATMENT PROTECTS MICROGLIA AND NEWLY GENERATED NEURONAL POPULATIONS IN A MOUSE MODEL OF CRANIAL RADIOTHERAPY

Abstract BACKGROUND Radiotherapy remains a cornerstone of the treatment of high-grade brain tumors. However, while lifesaving, it results in long-term complications in 50-96 % of the treated individuals, where cognitive deficits are particularly debilitating. Currently, no treatments or preventive strategies are available to avert these deficits. Lithium (Li), long used to treat bipolar affective disorder, has been shown to reduce radiation-induced cognitive deficits in rodent models by preventing apoptosis of the neuronal stem and progenitor cells in the hippocampus and stimulating their proliferation. This work aimed to further elucidate the mechanisms behind the protective and pro-regenerative actions of Li in the irradiated young brain. METHODS Postnatal day (PD) 21, C57BL6/J mice were injected intraperitoneally with Li chloride (4 mmol/kg) and kept on a Li carbonate-containing diet for 4 weeks. Control animals were injected with saline and administered an equivalent control diet. On PD 25, the animals were administered a single-dose whole-brain radiation of 8 Gy and were subsequently sacrificed at different time points, spanning from 2 weeks to 1 year. At sacrifice, the hippocampi were harvested for single-cell RNA sequencing using a novel, 2-step protocol to harvest viable cells of all types, including neurons. RESULTS The results showed that radiation triggered the expression of senescence-related genes in the hippocampal microglia (e.g., Cdkn1a, Ccl12), which Li has prevented through the activation of the Bcl2 family of genes. Moreover, they corroborate the protective effect of Li on newly generated hippocampal neurons, which undergo remodeling over time, leading to the emergence of new subpopulations. CONCLUSIONS This work represents another advancement towards understanding the action of Li in the irradiated brain and confirms its potential to become the first pharmacological treatment for radiation-induced complications.

Promotion of structural plasticity in area V2 of visual cortex prevents against object recognition memory deficits in aging and Alzheimer's disease rodents.

JOURNAL/nrgr/04.03/01300535-202408000-00038/figure1/v/2023-12-16T180322Z/r/image-tiff Memory deficit, which is often associated with aging and many psychiatric, neurological, and neurodegenerative diseases, has been a challenging issue for treatment. Up till now, all potential drug candidates have failed to produce satisfactory effects. Therefore, in the search for a solution, we found that a treatment with the gene corresponding to the RGS14414 protein in visual area V2, a brain area connected with brain circuits of the ventral stream and the medial temporal lobe, which is crucial for object recognition memory (ORM), can induce enhancement of ORM. In this study, we demonstrated that the same treatment with RGS14414 in visual area V2, which is relatively unaffected in neurodegenerative diseases such as Alzheimer's disease, produced long-lasting enhancement of ORM in young animals and prevent ORM deficits in rodent models of aging and Alzheimer's disease. Furthermore, we found that the prevention of memory deficits was mediated through the upregulation of neuronal arborization and spine density, as well as an increase in brain-derived neurotrophic factor (BDNF). A knockdown of BDNF gene in RGS14414-treated aging rats and Alzheimer's disease model mice caused complete loss in the upregulation of neuronal structural plasticity and in the prevention of ORM deficits. These findings suggest that BDNF-mediated neuronal structural plasticity in area V2 is crucial in the prevention of memory deficits in RGS14414-treated rodent models of aging and Alzheimer's disease. Therefore, our findings of RGS14414 gene-mediated activation of neuronal circuits in visual area V2 have therapeutic relevance in the treatment of memory deficits.

Behavioral, Genomic and Neurochemical Deficits Evoked by Neurotrauma in Adult Zebrafish (<i>Danio rerio</i>)

Traumatic brain injury (TBI) is a serious biomedical problem with high prevalence and mortality risks. Understanding TBI in traditional (e.g., rodent) animal models often presents challenges due to the complexity of their brain and its limited regenerative capabilities. Here, we present novel data obtained using the zebrafish TBI model based on a stab wound of telencephalon, aiming to investigate behavioral and molecular consequences of TBI in zebrafish. Four days following the injury, adult zebrafish displayed hypolocomotion in the novel seen tank test and impaired working memory in the Y-maze test, paralleling behavioral deficits in rodent models and human TBI patients. Molecular analyses of key genes involved in the inflammatory response and cell death pathways revealed a remarkable upregulation of the interferon-stimulated gene 15 (isg15) in the injured telencephalon, a general biomarker for neuronal damage. Furthermore, noradrenaline (but not dopamine or serotonin) levels in whole-brain tissue declined following TBI, likely contributing to the observed cognitive deficits and implicating neurotransmitter dysregulation in TBI pathogenesis.

Mouse Behavior on the Trial-Unique Nonmatching-to-Location (TUNL) Touchscreen Task Reflects a Mixture of Distinct Working Memory Codes and Response Biases.

The trial-unique nonmatching to location (TUNL) touchscreen task shows promise as a translational assay of working memory (WM) deficits in rodent models of autism, ADHD, and schizophrenia. However, the low-level neurocognitive processes that drive behavior in the TUNL task have not been fully elucidated. In particular, it is commonly assumed that the TUNL task predominantly measures spatial WM dependent on hippocampal pattern separation, but this proposition has not previously been tested. In this project, we tested this question using computational modeling of behavior from male and female mice performing the TUNL task (N = 163 across three datasets; 158,843 trials). Using this approach, we empirically tested whether TUNL behavior solely measured retrospective WM, or whether it was possible to deconstruct behavior into additional neurocognitive subprocesses. Overall, contrary to common assumptions, modeling analyses revealed that behavior on the TUNL task did not primarily reflect retrospective spatial WM. Instead, behavior was best explained as a mixture of response strategies, including both retrospective WM (remembering the spatial location of a previous stimulus) and prospective WM (remembering an anticipated future behavioral response) as well as animal-specific response biases. These results suggest that retrospective spatial WM is just one of a number of cognitive subprocesses that contribute to choice behavior on the TUNL task. We suggest that findings can be understood within a resource-rational framework, and use computational model simulations to propose several task-design principles that we predict will maximize spatial WM and minimize alternative behavioral strategies in the TUNL task.SIGNIFICANCE STATEMENT Touchscreen tasks represent a paradigm shift for assessment of cognition in nonhuman animals by automating large-scale behavioral data collection. Their main relevance, however, depends on the assumption of functional equivalence to cognitive domains in humans. The trial-unique, delayed nonmatching to location (TUNL) touchscreen task has revolutionized the study of rodent spatial working memory. However, its assumption of functional equivalence to human spatial working memory is untested. We leveraged previously untapped single-trial TUNL data to uncover a novel set of hierarchically ordered cognitive processes that underlie mouse behavior on this task. The strategies used demonstrate multiple cognitive approaches to a single behavioral outcome and the requirement for more precise task design and sophisticated data analysis in interpreting rodent spatial working memory.

XRT-05. LITHIUM PREVENTS RADIATION-INDUCED HIPPOCAMPAL MICROGLIA SENESCENCE IN A MOUSE MODEL OF PEDIATRIC CRANIAL RADIOTHERAPY

Abstract Radiotherapy is essential in the treatment of high-grade brain tumors. While often lifesaving, it typically results in long-term complications in 50-96 % of the treated individuals, where cognitive deficits are particularly debilitating, especially in pediatric patients. Although the survival rates have improved dramatically, there are currently no treatments or preventive strategies available to ameliorate the late cognitive complications. Lithium (Li), long used to treat patients with bipolar affective disorders, has been shown to reduce irradiation-induced cognitive deficits in rodent models by preventing apoptosis of the neuronal stem and progenitor cells in the hippocampus and stimulating their division. However, except for these anti-apoptotic and pro-neurogenic effects, there is limited understanding of how Li exerts its actions in the brain. This work aimed to further elucidate the mechanisms behind the protective action of Li in the irradiated young brain. To this end, post-natal day (PD) 21 C57BL6/J mice were intraperitoneally injected with lithium chloride (4 mmol/kg) and subsequently kept on a Li carbonate diet for 4 weeks. Control animals were injected with saline and administered an equivalent control diet. At PD25, the animals were subjected to a single dose of 8 Gy whole brain irradiation, and 6 weeks after irradiation, they were sacrificed, and their hippocampi were harvested for single-cell RNA sequencing and RT-qPCR. The attained results showed that irradiation induced hippocampal microglia senescence, as judged by the increased expression of the senescence-associated genes Cdkn1a, Cdkn2, Ccl12, C/Ebp and others in this cellular population. Conversely, Li prevented microglia senescence by activating the Bcl2 family of genes, as confirmed by the lower expression of the abovementioned senescence-associated genes in the Li-treated animals. These results provide the first step towards understanding the action of Li in the brain and confirm its potential to become the first pharmacological treatment for irradiation-induced late cognitive effects.

Therapeutic Potential of Fosgonimeton, a Small-Molecule Positive Modulator of the Neurotrophic HGF/MET Pathway, in Neurodegenerative Conditions (S14.008)

<h3>Objective:</h3> Evaluate the neurotrophic and neuroprotective effects of fosgonimeton, a small-molecule positive modulator of hepatocyte growth factor (HGF)/MET. <h3>Background:</h3> HGF signaling through the MET receptor promotes neural survival and function, making it a compelling target to combat neurodegeneration. We developed a series of small-molecule positive modulators of HGF/MET, including fosgonimeton, to target this neurotrophic system. <h3>Design/Methods:</h3> To demonstrate the neurotrophic effects of fosgonimeton, primary neurons were treated with the active metabolite of fosgonimeton (fosgo-AM) and assessed for synaptic count and neurite outgrowth. To evaluate neuroprotective effects, primary neurons were treated with fosgo-AM before exposure to relevant neurodegenerative insults, namely oxidative stress (hydrogen peroxide [H₂O₂]), neuroinflammation (lipopolysaccharide [LPS]), excitotoxicity (glutamate), and mitochondrial dysfunction (1-methyl-4-phenylpyridinium [MPP+]). The effects of fosgo-AM on protein aggregation in primary neuron cultures were evaluated via levels of phosphorylated tau (p-tau) induced by amyloid β (Aβ) toxicity in cortical neurons and α-synuclein aggregation induced by 6-hydroxydopamine (6-OHDA) in dopaminergic neurons. In vivo, the therapeutic usefulness of fosgonimeton was assessed for LPS-induced cognitive impairment in mice and 6-OHDA–induced motor deficits in rats. <h3>Results:</h3> In vitro, fosgo-AM significantly increased the number of synapses and neurite length in hippocampal and cortical neurons, respectively. Fosgo-AM was neuroprotective of cortical neurons subjected to oxidative, neuroinflammatory, excitotoxic, and mitochondrial challenges. Significant reduction in the number of disease biomarkers was observed with fosgo-AM treatment, including Aβ-induced p-tau accumulation in cortical neurons and 6-OHDA–induced α-synuclein aggregation in dopaminergic neurons. In vivo, fosgonimeton administration significantly attenuated LPS-induced cognitive impairment and 6-OHDA–induced motor deficits in rodent models. <h3>Conclusions:</h3> These results, from in vitro and in vivo systems, consistently support the broad application of fosgonimeton to neurodegenerative conditions. Collectively, our observations highlight the therapeutic potential of HGF/MET modulation in the management of neurodegenerative diseases that include AD and PD, supporting further clinical exploration of this approach. <b>Disclosure:</b> Dr. Reda has received personal compensation for serving as an employee of Athira Pharma, Inc. . Dr. Reda has stock in Athira Pharma, Inc. . Dr. Taylor has received personal compensation for serving as an employee of Athira Pharma, Inc. Dr. Taylor has stock in Athira Pharma, Inc.. Dr. Taylor has received intellectual property interests from a discovery or technology relating to health care. Dr. Johnston has received personal compensation for serving as an employee of Athira Pharma, Inc. Dr. Johnston has stock in Athira Pharma, Inc. An immediate family member of Dr. Johnston has stock in Athira Pharma, Inc. Dr. Johnston has received intellectual property interests from a discovery or technology relating to health care. Dr. Berthiaume has received personal compensation for serving as an employee of Athira Pharma. Dr. Berthiaume has stock in Athira Pharma. An immediate family member of Dr. Berthiaume has stock in Athira Pharma. Dr. Setti has received personal compensation for serving as an employee of Athira Pharma. Dr. Setti has stock in Athira Pharma. Dr. Church has received personal compensation for serving as an employee of Athira Pharma. Dr. Church has stock in Athira Pharma. Dr. Church has received intellectual property interests from a discovery or technology relating to health care.

Evidence for Prepulse Inhibition of Visually Evoked Motor Response in Drosophila melanogaster.

Prepulse inhibition (PPI) is a widely investigated behavior to study the mechanisms of disorders such as anxiety, schizophrenia, and bipolar mania. PPI has been observed across various vertebrate and invertebrate species; however, it has not yet been reported in adult Drosophila melanogaster. In this study, we describe the first detection of PPI of visually evoked locomotor arousal in flies. To validate our findings, we demonstrate that PPI in Drosophila can be partially reverted by the N-methyl D-aspartate (NMDA) receptor antagonist MK-801, known for inducing sensorimotor gating deficits in rodent models. Additionally, we show that the visually evoked response can be inhibited by multiple stimuli presentation, which can also be affected by MK-801. Given the versatility of Drosophila as a model organism for genetic screening and analysis, our results suggest that high-throughput behavioral screenings of adult flies can become a valuable tool for investigating the mechanisms behind PPI.

Running from Stress: Neurobiological Mechanisms of Exercise-Induced Stress Resilience.

Chronic stress, even stress of a moderate intensity related to daily life, is widely acknowledged to be a predisposing or precipitating factor in neuropsychiatric diseases. There is a clear relationship between disturbances induced by stressful stimuli, especially long-lasting stimuli, and cognitive deficits in rodent models of affective disorders. Regular physical activity has a positive effect on the central nervous system (CNS) functions, contributes to an improvement in mood and of cognitive abilities (including memory and learning), and is correlated with an increase in the expression of the neurotrophic factors and markers of synaptic plasticity as well as a reduction in the inflammatory factors. Studies published so far show that the energy challenge caused by physical exercise can affect the CNS by improving cellular bioenergetics, stimulating the processes responsible for the removal of damaged organelles and molecules, and attenuating inflammation processes. Regular physical activity brings another important benefit: increased stress robustness. The evidence from animal studies is that a sedentary lifestyle is associated with stress vulnerability, whereas a physically active lifestyle is associated with stress resilience. Here, we have performed a comprehensive PubMed Search Strategy for accomplishing an exhaustive literature review. In this review, we discuss the findings from experimental studies on the molecular and neurobiological mechanisms underlying the impact of exercise on brain resilience. A thorough understanding of the mechanisms underlying the neuroprotective potential of preconditioning exercise and of the role of exercise in stress resilience, among other things, may open further options for prevention and therapy in the treatment of CNS diseases.

SIRT1 Activation Promotes Long-Term Functional Recovery After Subarachnoid Hemorrhage in Rats.

An increase in sirtuin 1 (SIRT1) reportedly attenuates early brain injury, delayed cerebral ischemia, and short-term neurologic deficits in rodent models of subarachnoid hemorrhage (SAH). This study investigates the effect of resveratrol, a SIRT1 activator, on long-term functional recovery in a clinically relevant rat model of SAH. Thirty male Wistar rats were subjected to fresh arterial blood injection into the prechiasmatic space and randomized to receive 7days of intraperitoneal resveratrol (20mg/kg) or vehicle injections. Body weight and rotarod performance were measured on days 0, 3, 7, and 34 post SAH. The neurologic score was assessed 7 and 34days post SAH. Morris water maze performance was evaluated 29-33days post SAH. Brain SIRT1 activity and CA1 neuronal survival were also assessed. Blood pressure rapidly increased in all SAH rats, and no between-group differences in blood pressure, blood gases, or glucose were detected. SAH induced weight loss during the first 7days, which gradually recovered in both groups. Neurologic score and rotarod performance were significantly improved after resveratrol treatment at 34days post SAH (p = 0.01 and 0.04, respectively). Latency to find the Morris water maze hidden platform was shortened (p = 0.02). In the resveratrol group, more CA1 neurons survived following SAH (p = 0.1). An increase in brain SIRT1 activity was confirmed in the resveratrol group (p < 0.05). Treatment with resveratrol for 1week significantly improved the neurologic score, rotarod performance, and latency to find the Morris water maze hidden platform 34days post SAH. These findings indicate that SIRT1 activation warrants further investigation as a mechanistic target for SAH therapy.

Peptide LCGA-17 Attenuates Behavioral and Neurochemical Deficits in Rodent Models of PTSD and Depression.

We have previously described the LCGA-17 peptide as a novel anxiolytic and antidepressant candidate that acts through the α2δ VGCC (voltage-gated calcium channel) subunit with putative synergism with GABA-A receptors. The current study tested the potential efficacy of acute and chronic intranasal (i.n.) LCGA-17 (0.05 mg/kg and 0.5 mg/kg) in rats on predator odor-induced conditioned place aversion (POCPA), a model of post-traumatic stress disorder (PTSD), and chronic unpredictable stress (CUS) that produce a range of behavioral and physiological changes that parallel symptoms of depression in humans. CUS and LCGA-17 treatment effects were tested in the sucrose preference (SPT) social interaction (SI), female urine sniffing (FUST), novelty-suppressed feeding (NSFT), and forced swim (FST) tests. Analysis of the catecholamines content in brain structures after CUS was carried out using HPLC. The efficacy of i.n. LCGA-17 was also assessed using the Elevated plus-maze (EPM) and FST. Acute LCGA-17 administration showed anxiolytic and antidepressant effects in EPM and FST, similar to diazepam and ketamine, respectively. In the POCPA study, LCGA-17 significantly reduced place aversion, with efficacy greater than doxazosin. After CUS, chronic LCGA-17 administration reversed stress-induced alterations in numerous behavioral tests (SI, FUST, SPT, and FST), producing significant anxiolytic and antidepressant effects. Finally, LCGA-17 restored the norepinephrine levels in the hippocampus following stress. Together, these results support the further development of the LCGA-17 peptide as a rapid-acting anxiolytic and antidepressant.

Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons.

After stroke, there is a rapid necrosis of all cells in the infarct, followed by a delayed loss of neurons both in brain areas surrounding the infarct, known as ‘selective neuronal loss’, and in brain areas remote from, but connected to, the infarct, known as ‘secondary neurodegeneration’. Here we review evidence indicating that this delayed loss of neurons after stroke is mediated by the microglial phagocytosis of stressed neurons. After a stroke, neurons are stressed by ongoing ischemia, excitotoxicity and/or inflammation and are known to: (i) release “find-me” signals such as ATP, (ii) expose “eat-me” signals such as phosphatidylserine, and (iii) bind to opsonins, such as complement components C1q and C3b, inducing microglia to phagocytose such neurons. Blocking these factors on neurons, or their phagocytic receptors on microglia, can prevent delayed neuronal loss and behavioral deficits in rodent models of ischemic stroke. Phagocytic receptors on microglia may be attractive treatment targets to prevent delayed neuronal loss after stroke due to the microglial phagocytosis of stressed neurons.

Reduced Synaptic Transmission and Intrinsic Excitability of a Subtype of Pyramidal Neurons in the Medial Prefrontal Cortex in a Mouse Model of Alzheimer's Disease.

Abnormal morphology and function of neurons in the prefrontal cortex (PFC) are associated with cognitive deficits in rodent models of Alzheimer's disease (AD), particularly in cortical layer-5 pyramidal neurons that integrate inputs from different sources and project outputs to cortical or subcortical structures. Pyramidal neurons in layer-5 of the PFC can be classified as two subtypes depending on the inducibility of prominent hyperpolarization-activated cation currents (h-current). However, the differences in the neurophysiological alterations between these two subtypes in rodent models of AD remain poorly understood. To investigate the neurophysiological alterations between two subtypes of pyramidal neurons in hAPP-J20 mice, a transgenic model for early onset AD. The synaptic transmission and intrinsic excitability of pyramidal neurons were investigated using whole-cell patch recordings. The morphological complexity of pyramidal neurons was detected by biocytin labelling and subsequent Sholl analysis. We found reduced synaptic transmission and intrinsic excitability of the prominent h-current (PH) cells but not the non-PH cells in hAPP-J20 mice. Furthermore, the function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which mediated h-current was disrupted in the PH cells of hAPP-J20 mice. Sholl analysis revealed that PH cells had less dendritic intersections in hAPP-J20 mice comparing to control mice, implying that a lower morphological complexity might contribute to the reduced neuronal activity. These results suggest that the PH cells in the medial PFC may be more vulnerable to degeneration in hAPP-J20 mice and play a sustainable role in frontal dysfunction in AD.

Neuroprotection of minocycline by inhibition of extracellular matrix metalloproteinase inducer expression following intracerebral hemorrhage in mice

Intracerebral hemorrhage (ICH) is a severe neurological dysfunction and a medical emergency with a high mortality rate. Minocycline ameliorates deficits in rodent models of acute and chronic neurological diseases. However, the role of minocycline in ICH remains unclear. The extracellular matrix metalloproteinase inducer (EMMPRIN) is a key inflammatory mediator in some neurological diseases, triggering matrix metalloproteinases (MMPs) production. In this study, we aimed to use minocycline to inhibit EMMPRIN and thus the activity of MMPs. Male adult C57BL/6 mice were injected with collagenase type VII or saline into the right basal ganglia and euthanized at different time points. The minocycline was intraperitoneally injected once every 12 h for three days to block the expression of EMMPRIN from two hours after ICH. We found that breakdown of the BBB was most severe 3 days after ICH. The minocycline treatment significantly decreased EMMPRIN and MMP-9 expression, reduced zonula occludens-1 and occludin, and alleviated BBB disruption. Moreover, minocycline treatment displayed a lower brain water content, lesser neurological dysfunction, and smaller injury volume on day 3 than those of the vehicle-treated group. Minocycline also inhibited the activation of microglia/macrophages, infiltration of neutrophils, and production of inflammatory mediators, including tumor necrosis factor alpha and interleukin-1beta. The current study shows that minocycline exhibits protective roles in ICH by decreasing EMMPRIN and MMP-9 expression, alleviating BBB disruption, inhibiting neuroinflammation, and reducing neuronal degeneration and death.

The Touchscreen-Based Trial-Unique, Nonmatching-To-Location (TUNL) Task as a Measure of Working Memory and Pattern Separation in Rats and Mice.

The TUNL task is an automated touchscreen task used to evaluate the cognitive processes involved in working memory (WM) and spatial pattern separation in rodents. Both rats and mice can be used. To elicit working memory processes, the rodent must distinguish between a sample (familiar) light stimulus and a novel light stimulus after a delay. With a correct selection, the rodent will receive a food reward. A major benefit of TUNL compared to other similar tasks is the circumvention of spatial "mediating strategies" that the rodent may use to supplement or replace working memory processes to complete the task successfully. Each trial is 'unique', as the stimuli are pseudo-randomized between trials in an array of spatial locations. The TUNL task uses a progression of six training steps to teach the rodent the associated rules necessary to complete the full task. Task performance is typically measured by trials completed and by accuracy. Task accuracy can be evaluated across various spatial separations to engage hippocampal-dependent processes involved in spatial pattern separation. The latency between trial responses can also be evaluated, with food reward collection latency as a measure of motivation. The TUNL task can be used to assess working memory and cognitive deficits in rodent models with neurodegenerative and neurological disorders, providing a valuable tool to screen for new treatment options, in addition to assessing basic neurobiology. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Handling and habituation prior to training Basic Protocol 2: Initial Touch Training Basic Protocol 3: Must Touch Training Basic Protocol 4: Must Initiate Training Basic Protocol 5: Punish Incorrect Training Basic Protocol 6: Initial TUNL Training Basic Protocol 7: Full TUNL Training Support Protocol 1: Using ABET II touch program Support Protocol 2: Preparation of touchscreen chambers prior to training sessions.

Examination of cortically projecting cholinergic neurons following exercise and environmental intervention in a rodent model of fetal alcohol spectrum disorders.

Up to 1 in 5 infants in the United States are exposed to alcohol prenatally, resulting in neurodevelopmental deficits categorized as fetal alcohol spectrum disorders (FASD). Choline supplementation ameliorates some deficits, suggesting that alcohol exposure (AE) perturbs cholinergic neurotransmission and development. Behavioral interventions, which upregulate cholinergic neurotransmission, rescue cognitive deficits in rodent models of FASD. We investigated the impacts of two interventions (either wheel-running (WR) or "super intervention," WR plus exposure to a complex environment) on cholinergic neuronal morphology in the nucleus basalis of Meynert (NBM), the source of cortical cholinergic input, and prefrontal cortex (PFC) in a rodent model of FASD. One third of the total 47 male pups received intragastric intubation of ethanol in milk substitute during postnatal days (PD) 4-9. Another third served as sham-intubated procedural controls while the final third served as suckle controls. Rats from each group were exposed to either intervention during PD 30-72. Choline acetyltransferase (ChAT+ ) and acetylcholinesterase staining were used to quantify cholinergic neuron number, soma volume, and axon number. Our data indicate a main effect of postnatal treatment on ChAT+ neuron number in NBM in adulthood. Post hoc analysis demonstrates that ChAT+ neuron number is reduced in AE compared to suckle control rodents (p < .01). We examined the cytoarchitectonics of cholinergic neurons in NBM and PFC in adulthood following early postnatal AE and two interventions. We show that AE reduces ChAT+ neuron number in NBM, and this is not mitigated by either intervention.

In Vivo Effective Connectivity of Mouse Ventral Hippocampus With Medial Prefrontal Cortex Microcircuits

Neuronal communication between rodent ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) supports cognitive functions such spatial working memory. Impaired communication between these structures underlies cognitive deficits in rodent models of predisposition to schizophrenia. Neural activity in direct vHPC-mPFC projections, as well as mPFC somatostatin-positive (SST+) interneurons, are essential for normal vHPC-mPFC communication and spatial working memory. Whether and how these two neural substrates interact to support vHPC-mPFC communication remains unclear.

A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer's brain.

It is increasingly accepted that early cognitive impairment in Alzheimer's disease results in considerable part from synaptic dysfunction caused by the accumulation of a range of oligomeric assemblies of amyloid β-protein (Aβ). Most studies have used synthetic Aβ peptides to explore the mechanisms of memory deficits in rodent models, but recent work suggests that Aβ assemblies isolated from human (AD) brain tissue are far more potent and disease-relevant. Although reductionist experiments show Aβ oligomers to impair synaptic plasticity and neuronal viability, the responsible mechanisms are only partly understood. Glutamatergic receptors, GABAergic receptors, nicotinic receptors, insulin receptors, the cellular prion protein, inflammatory mediators, and diverse signaling pathways have all been suggested. Studies using AD brain-derived soluble Aβ oligomers suggest that only certain bioactive forms (principally small, diffusible oligomers) can disrupt synaptic plasticity, including by binding to plasma membranes and changing excitatory-inhibitory balance, perturbing mGluR, PrP, and other neuronal surface proteins, down-regulating glutamate transporters, causing glutamate spillover, and activating extrasynaptic GluN2B-containing NMDA receptors. We synthesize these emerging data into a mechanistic hypothesis for synaptic failure in Alzheimer's disease that can be modified as new knowledge is added and specific therapeutics are developed.

Molecular causes of sex-specific deficits in rodent models of neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) such as intellectual disability and autism spectrum disorder consistently show a male bias in prevalence, but it remains unclear why males and females are affected with different frequency. While many behavioral studies of transgenic NDD models have focused only on males, the requirement by the National Institutes of Health to consider sex as a biological variable has promoted the comparison of male and female performance in wild‐type and mutant animals. Here, we review examples of rodent models of NDDs in which sex‐specific deficits were identified in molecular, physiological, and/or behavioral responses, showing sex differences in susceptibility to disruption of genes mutated in NDDs. Haploinsufficiency in genes involved in mechanisms such as synaptic function (GABRB3 and NRXN1), chromatin remodeling (CHD8, EMHT1, and ADNP), and intracellular signaling (CC2D1A and ERK1) lead to more severe behavioral outcomes in males. However, in the absence of behavioral deficits, females can still present with cellular and electrophysiological changes that could be due to compensatory mechanisms or differential allocation of molecular and cellular functions in the two sexes. By contrasting these findings with mouse models where females are more severely affected (MTHFR and AMBRA1), we propose a framework to approach the study of sex‐specific deficits possibly leading to sex bias in NDDs.

Altered avalanche dynamics in a developmental NMDAR hypofunction model of cognitive impairment

Disturbed activity patterns in cortical networks contribute to the pathophysiology of schizophrenia (SZ). Several lines of evidence implicate NMDA receptor hypofunction in SZ, and blocking NMDA receptor signaling during early neurodevelopment produces cognitive deficits in rodent models that resemble those seen in schizophrenic patients. However, the altered network dynamics underlying these cognitive impairments largely remain to be characterized, especially at the cellular level. Here, we use in vivo two-photon calcium imaging to describe pathological dynamics, occurring in parallel with cognitive dysfunction, in a developmental NMDA receptor hypofunction model. We observed increased synchrony and specific alterations in spatiotemporal activity propagation, which could be causally linked to a previously unidentified persistent bursting phenotype. This phenotype was rescued by acute treatment with the NMDA receptor co-agonist D-serine or the GABAB receptor agonist baclofen, which similarly rescued working memory performance. It was not reproduced by optogenetic inhibition of fast-spiking interneurons. These results provide novel insight into network-level abnormalities mediating the cognitive impairment induced by NMDA receptor hypofunction.

The final frontier: Transient microglia reduction after cosmic radiation exposure mitigates cognitive impairments and modulates phagocytic activity.

Microglia are the primary immune element within the brain, which are responsible for monitoring synapse function and neuron health. Exposure to cosmic radiation has the potential to cause long-term cognitive deficits in rodent models and therefore indicates a difficult challenge for future astronauts piloting interplanetary travel. Here, we discuss the potential of transient microglia depletion after the injury to ameliorate the harsh microenvironment of the brain and eliminate any potential long-term cognitive effects. Repopulation of microglia enables phagocytic phenotypes to be circumvented, via the reduction of Phagocytic and lysosomal markers, potentially being responsible for increased neuroprotection. Brief depletion of microglia after irradiation mitigated the development of any long-term memory deficits, comparable to healthy animals. Chronically, microglial levels were not affected by cosmic radiation followed by temporary microglia depletion. Following repopulation, improved recognition memory was paralleled by downregulated complement receptor C5aR. Preserved synapse function also demonstrated the therapeutic ability of microglia depletion as it corresponded with fewer phagocytic microglia phenotypes. The understanding of long-term radiation-induced cognitive impairments is vital for the protection of future astronauts and equally as important for current cancer patients. Temporary microglia depletion showed promise in preventing any deleterious cognitive impairments following exposure to elements of cosmic radiation, such as helium and high-charge nuclei.