Sex-Specific Effects of Anxiety on Cognition and Activity-Dependent Neural Networks: Insights From (Female) Mice and (Wo)men.

Background: Neuropsychiatric symptoms, such as depression and anxiety, are observed in 90% of patients with Alzheimer's disease (AD), two-thirds of whom are women. Neuropsychiatric symptoms usually manifest long before AD onset creating a therapeutic opportunity. Here, we examined the impact of anxiety on AD progression and the underlying brainwide neuronal mechanisms.

A tale of two receptors: simultaneous targeting of NMDARs and 5-HT Rs exerts additive effects against stress.

Background: Serotonin (5-HT) receptors and -methyl-D-aspartate receptors (NMDARs) have both been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of ( , )-ketamine, an NMDAR antagonist, and prucalopride, a serotonin type IV receptor (5-HT R) agonist, would have additive effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia.

Methods: A single injection of saline (Sal), ( , )-ketamine (K), prucalopride (P), or a combined dose of ( , )-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes.

Benzodiazepine-induced anterograde amnesia: detrimental side effect to novel study tool.

Benzodiazepines (BZDs) are anxiolytic drugs that act on GABAa receptors and are used to treat anxiety disorders. However, these drugs come with the detrimental side effect of anterograde amnesia, or the inability to form new memories. In this review we discuss, behavioral paradigms, sex differences and hormonal influences affecting BZD-induced amnesia, molecular manipulations, including the knockout of GABAa receptor subunits, and regional studies utilizing lesion and microinjection techniques targeted to the hippocampus and amygdala.

Sex-Specific Effects of Anxiety on Cognition and Activity-Dependent Neural Networks: Insights from (Female) Mice and (Wo)Men.

Introduction: Neuropsychiatric symptoms (NPS), such as depression and anxiety, are observed in 90% of Alzheimer's disease (AD) patients, two-thirds of whom are women. NPS usually manifest long before AD onset creating a therapeutic opportunity. Here, we examined the impact of anxiety on AD progression and the underlying brain-wide neuronal mechanisms.

Traumatic Brain Injury-Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine.

Background: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization and the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI.

Traumatic brain injury-induced fear generalization in mice involves hippocampal memory trace dysfunction and is alleviated by ( )-ketamine.

Introduction: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization, the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI.

Differential Effects of Human P301L Tau Expression in Young versus Aged Mice.

The greatest risk factor for developing Alzheimer's disease (AD) is increasing age. Understanding the changes that occur in aging that make an aged brain more susceptible to developing AD could result in novel therapeutic targets. In order to better understand these changes, the current study utilized mice harboring a regulatable mutant P301L human transgene (rTg(TauP301L)4510), in which P301L tau expression can be turned off or on by the addition or removal of doxycycline in the drinking water.

Fluoroethylnormemantine, a Novel NMDA Receptor Antagonist, for the Prevention and Treatment of Stress-Induced Maladaptive Behavior.

Background: Major depressive disorder is a common, recurrent illness. Recent studies have implicated the NMDA receptor in the pathophysiology of major depressive disorder. (R,S)-ketamine, an NMDA receptor antagonist, is an effective antidepressant but has numerous side effects.

Author Correction: Divergence in the metabolome between natural aging and Alzheimer's disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Behavioral and neurobiological effects of GnRH agonist treatment in mice-potential implications for puberty suppression in transgender individuals.

In the United States, ~1.4 million individuals identify as transgender. Many transgender adolescents experience gender dysphoria related to incongruence between their gender identity and sex assigned at birth.

Divergence in the metabolome between natural aging and Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disorder and one of the leading causes of death in the United States. Although amyloid plaques and fibrillary tangles are hallmarks of AD, research suggests that pathology associated with AD often begins 20 or more years before symptoms appear. Therefore, it is essential to identify early-stage biomarkers in those at risk for AD and age-related cognitive decline (ARCD) in order to develop preventative treatments.

The role of APOE4 in Alzheimer's disease: strategies for future therapeutic interventions.

Alzheimer's disease (AD) is the leading cause of dementia affecting almost 50 million people worldwide. The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor for late-onset AD cases, with homozygous carriers being approximately 15-times more likely to develop the disease. With 25% of the population being carriers, understanding the role of this allele in AD pathogenesis and pathophysiology is crucial.

Prophylactic (R,S)-ketamine selectively protects against inflammatory stressors.

Individuals with peripheral inflammation are a particularly vulnerable population for developing depression and are also more resistant towards traditional antidepressants. This signals the need for novel drugs that can effectively treat this patient population. Recently, we have demonstrated that (R,S)-ketamine is a prophylactic against a variety of stressors, but have yet to test if it is protective against inflammatory-induced vulnerability to a stressor.

Alterations in Hippocampal Activity and Alzheimer's Disease.

The aging population and those with amnestic mild cognitive impairment (aMCI) are at increased risk for developing Alzheimer's disease (AD). Individuals with aMCI in particular may display pathological changes in brain function that may ultimately result in a diagnosis of AD. This review focuses specifically on hippocampal hyperexcitability, a pathology that is sometimes detectable years before diagnosis, which has been observed in individuals with aMCI.

Using Enzyme-based Biosensors to Measure Tonic and Phasic Glutamate in Alzheimer's Mouse Models.

Neurotransmitter disruption is often a key component of diseases of the central nervous system (CNS), playing a role in the pathology underlying Alzheimer's disease, Parkinson's disease, depression, and anxiety. Traditionally, microdialysis has been the most common (lauded) technique to examine neurotransmitter changes that occur in these disorders. But because microdialysis has the ability to measure slow 1-20 minute changes across large areas of tissue, it has the disadvantage of invasiveness, potentially destroying intrinsic connections within the brain and a slow sampling capability.

Peripheral viral challenge elevates extracellular glutamate in the hippocampus leading to seizure hypersusceptibility.

Peripheral viral infections increase seizure propensity and intensity in susceptible individuals. We have modeled this comorbidity by demonstrating that the acute phase response instigated by an intraperitoneal (i.p.

Peripherally restricted viral challenge elevates extracellular glutamate and enhances synaptic transmission in the hippocampus.

Peripheral infections increase the propensity and severity of seizures in susceptible populations. We have previously shown that intraperitoneal injection of a viral mimic, polyinosinic-polycytidylic acid (PIC), elicits hypersusceptibility of mice to kainic acid (KA)-induced seizures. This study was undertaken to determine whether this seizure hypersusceptibility entails alterations in glutamate signaling.

Riluzole rescues alterations in rapid glutamate transients in the hippocampus of rTg4510 mice.

Those at risk for Alzheimer's disease (AD) often exhibit hippocampal hyperexcitability in the years preceding diagnosis. Our previous work with the rTg(TauP301L)4510 tau mouse model of AD suggests that this increase in hyperexcitability is likely mediated by an increase in depolarization-evoked glutamate release and a decrease in glutamate uptake, alterations of which correlate with learning and memory deficits. Treatment with riluzole restored glutamate regulation and rescued memory deficits in the TauP301L model.

Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression.

Hyperexcitability of the hippocampus is a commonly observed phenomenon in the years preceding a diagnosis of Alzheimer's disease (AD). Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.

The role of the tripartite glutamatergic synapse in the pathophysiology of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear.

P301L tau expression affects glutamate release and clearance in the hippocampal trisynaptic pathway.

Individuals at risk of developing Alzheimer's disease (AD) often exhibit hippocampal hyperexcitability. A growing body of evidence suggests that perturbations in the glutamatergic tripartite synapse may underlie this hyperexcitability. Here, we used a tau mouse model of AD (rTg(TauP301L)4510) to examine the effects of tau pathology on hippocampal glutamate regulation.

Effects of an α5GABAA inverse agonist on MK-801-induced learning deficits in an incremental repeated acquisition task.

N-methyl-D-aspartate receptors (NMDARs) are essential for several kinds of synaptic plasticity and play a critical role in learning and memory. Deficits in NMDAR functioning may be partially responsible for the learning and memory deficits associated with aging and numerous diseases. Administration of MK-801, a noncompetitive NMDAR antagonist, is commonly used as a preclinical model of NMDAR dysfunction.

Effect size of memory deficits in mice with adult-onset P301L tau expression.

Transgenic mice expressing mutations in tau have yielded essential discoveries for Alzheimer's disease. One of the most commonly used tau mouse models is the tet-off Tg(tauP301L)4510 model that expresses P301L human tau driven by the calcium-calmodulin kinase IIα (CaMKIIα) promoter system. Tau expression in this model is regulatable, allowing for suppression of mutant tau expression until adulthood and prevention of possible developmental alterations resulting from P301L tau expression during development.