The Effects of Locus Coeruleus Optogenetic Stimulation on Global Spatiotemporal Patterns in Rats.

Whole-brain intrinsic activity as detected by resting-state fMRI can be summarized by three primary spatiotemporal patterns. These patterns have been shown to change with different brain states, especially arousal. The noradrenergic locus coeruleus (LC) is a key node in arousal circuits and has extensive projections throughout the brain, giving it neuromodulatory influence over the coordinated activity of structurally separated regions. In this study, we used optogenetic-fMRI in rats to investigate the impact of LC stimulation on the global signal and three primary spatiotemporal patterns. We report small, spatially specific changes in global signal distribution as a result of tonic LC stimulation, as well as regional changes in spatiotemporal patterns of activity at 5 Hz tonic and 15 Hz phasic stimulation. We also found that LC stimulation had little to no effect on the spatiotemporal patterns detected by complex principal component analysis. These results show that the effects of LC activity on the BOLD signal in rats may be small and regionally concentrated, as opposed to widespread and globally acting.

Aging leads to sex-dependent effects on pair bonding and increased number of oxytocin-producing neurons in monogamous prairie voles.

Pair bonds powerfully modulate health, which becomes particularly important when facing the detrimental effects of aging. To examine the impact of aging on relationship formation and response to loss, we examined behavior in 6-, 12-, and 18-month male and female prairie voles, a monogamous species that forms mating-based pair bonds. We found that older males (18-months) bonded quicker than younger voles, while similarly aged female voles increased partner directed affiliative behaviors. Supporting sex differences in bonding behaviors, we found that males were more likely to sample both partner and novel voles while females were more likely to display partner preference during the initial 20 minutes of the test. Using partner separation to study loss, we observed an erosion of partner preference only in 12-month females, but an overall decrease in partner-directed affiliation in females across all groups, but not in males. Finally, we found that the number of oxytocin, but not vasopressin, cells in the paraventricular hypothalamus increased during aging. These results establish prairie voles as a novel model to study the effects of normal and abnormal aging on pair bonding. Highlights: 18-month male voles demonstrate accelerated bond formation18-month female voles increase partner-directed huddling after 2 wksBonds erode faster in 12-month female voles after partner separationFemale behavior from partner preference tests is reflected in free interactionThe number of paraventricular hypothalamus oxytocin cells increase during aging.

Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline.

Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aß), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar "Western" diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.

Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease.

Hyperphosphorylated tau in the locus coeruleus (LC) is ubiquitous in prodromal Alzheimer's disease (AD), and LC neurons degenerate as AD progresses. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons are unknown. We assessed single unit LC activity in anesthetized wild-type (WT) and TgF344-AD rats at 6 months, which represents a prodromal stage when LC neurons are the only cells containing hyperphosphorylated tau in TgF344-AD animals, and at 15 months when amyloid-ß (Aß) and tau pathology are both abundant in the forebrain. At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates but showed elevated spontaneous bursting properties. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and 15-month transgenic rats showing hypoactivity. Early LC hyperactivity is consistent with appearance of prodromal neuropsychiatric symptoms and is followed by LC hypoactivity which contributes to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD.

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease.

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg, one week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms.

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

A novel link between locus coeruleus activity and amyloid-related cognitive decline.

Recent work from Prokopiou, Engels-Domínguez et al. assessed locus coeruleus (LC) activity and its functional connectivity (FC) to forebrain regions during a novelty task in cognitively unimpaired adult individuals with varying degrees of amyloid deposition. Novelty increased LC activity and LC FC, but lower responses on these measures were associated with steeper cognitive decline in amyloid-positive individuals.

Consequences of Hyperphosphorylated Tau in the Locus Coeruleus on Behavior and Cognition in a Rat Model of Alzheimer's Disease.

BACKGROUND: The locus coeruleus (LC) is one of the earliest brain regions to accumulate hyperphosphorylated tau, but a lack of animal models that recapitulate this pathology has hampered our understanding of its contributions to Alzheimer's disease (AD) pathophysiology. OBJECTIVE: We previously reported that TgF344-AD rats, which overexpress mutant human amyloid precursor protein and presenilin-1, accumulate early endogenous hyperphosphorylated tau in the LC. Here, we used TgF344-AD rats and a wild-type (WT) human tau virus to interrogate the effects of endogenous hyperphosphorylated rat tau and human tau in the LC on AD-related neuropathology and behavior. METHODS: Two-month-old TgF344-AD and WT rats received bilateral LC infusions of full-length WT human tau or mCherry control virus driven by the noradrenergic-specific PRSx8 promoter. Rats were subsequently assessed at 6 and 12 months for arousal (sleep latency), anxiety-like behavior (open field, elevated plus maze, novelty-suppressed feeding), passive coping (forced swim task), and learning and memory (Morris water maze and fear conditioning). Hippocampal microglia, astrocyte, and AD pathology were evaluated using immunohistochemistry. RESULTS: In general, the effects of age were more pronounced than genotype or treatment; older rats displayed greater hippocampal pathology, took longer to fall asleep, had reduced locomotor activity, floated more, and had impaired cognition compared to younger animals. TgF344-AD rats showed increased anxiety-like behavior and impaired learning and memory. The tau virus had negligible influence on most measures. CONCLUSION: Effects of hyperphosphorylated tau on AD-like neuropathology and behavioral symptoms were subtle. Further investigation of different forms of tau is warranted.

What's That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease.

The locus coeruleus (LC) has long been underappreciated for its role in the pathophysiology of Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative disorders. While AD and PD are distinct in clinical presentation, both are characterized by prodromal protein aggregation in the LC, late-stage degeneration of the LC, and comorbid conditions indicative of LC dysfunction. Many of these early studies were limited to post-mortem histological techniques due to the LC's small size and location deep in the brainstem. Thus, there is a growing interest in utilizing in vivo imaging of the LC as a predictor of preclinical neurodegenerative processes and biomarker of disease progression. Simultaneously, neuroimaging in animal models of neurodegenerative disease holds promise for identifying early alterations to LC circuits, but has thus far been underutilized. While still in its infancy, a handful of studies have reported effects of single gene mutations and pathology on LC function in disease using various neuroimaging techniques. Furthermore, combining imaging and optogenetics or chemogenetics allows for interrogation of network connectivity in response to changes in LC activity. The purpose of this article is twofold: (1) to review what magnetic resonance imaging (MRI) and positron emission tomography (PET) have revealed about LC dysfunction in neurodegenerative disease and its potential as a biomarker in humans, and (2) to explore how animal models can be used to test hypotheses derived from clinical data and establish a mechanistic framework to inform LC-focused therapeutic interventions to alleviate symptoms and impede disease progression.

Female rats express habitual behavior earlier in operant training than males.

Habitual behavior can be advantageous by increasing the availability of cognitive resources for use in other tasks. However, habitual behaviors are problematic when they are coopted to prolong the maladaptive responding present in several psychopathologies such as substance abuse, dysregulated fear responding in posttraumatic stress disorder, and obsessive-compulsive disorder. Although sex differences exist in the occurrence or progression of these psychopathologies, there are no studies that compare the development of habitual behavior systematically in male and female animals. In the present study, male and female rats were identically trained on a variable interval 30-s (VI 30-s) schedule of reinforcement to nose-poke for sucrose pellet reinforcers. Subsequently, the sucrose was devalued in one half of the animals by pairing its presentation with injections of lithium chloride (LiCl) to induce nausea, thus conditioning a taste aversion. Habitual behavior was operationalized as continued operant responding in an extinction test following devaluation of the sucrose reinforcer. Successful devaluation was confirmed with both a consumption and reacquisition test. Given identical training to 240 sucrose pellets, female rats demonstrate habitual behavior whereas male rats remain goal-directed. Additionally, females are habitual after 200 or 160 reinforcers earned on a VI 30-s schedule, but remain goal-directed at 120 and 80 reinforcers on this schedule. These data suggest that behavioral flexibility may be compromised in female rats compared to males due to accelerated habit formation in females. These results are important because sex differences are present in several psychopathologies, which may be related to differences in the development of habitual behavior. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

New Pharmacological Approaches to Treating Non-Motor Symptoms of Parkinson's Disease.

PURPOSE OF REVIEW: Non-motor symptoms in patients with Parkinson's Disease (PD) are better predictors of quality of life changes, caregiver burden, and mortality than motor symptoms. Levodopa has limited, and sometimes detrimental, effects on these symptoms. In this review we discuss recent evidence on pharmacological treatments for non-motor symptoms. RECENT FINDINGS: Breakthroughs have been made in the treatment of psychosis and sleep dysfunction. Pimavanserin has become the first FDA approved drug for PD psychosis. There is also new research supporting cholinesterase inhibitors for sleep disorders in PD. Other studies, including several novel treatments, have shown mixed results for apathy, depression, and fatigue. SUMMARY: Further research is needed to develop treatments for non-motor symptoms in PD. Preclinical and postmortem studies indicate that non-motor symptoms in PD may arise from pathology in non-dopamine systems. Although sometimes used off-label, therapies that target such systems have been under-utilized in treating non-motor symptoms and warrant further clinical investigation.

Science or fiction: use of nesiritide as a first-line agent?

Nesiritide is an effective agent for the treatment of decompensated CHF. However, the VMAC trial shows that the agent's efficacy and safety are actually more similar than dissimilar to those of nitroglycerin. Indeed, objective reviews have placed nesiritide as a second-line agent behind current standard drug therapy. Finally, nesiritide is approximately 40 times the purchase price of standard agents such as nitroglycerin. For these reasons, we feel that nesiritide should not be considered as first-line therapy. Reflecting this notion, one institution has implemented a protocol that recommends administration of nitroglycerin and intravenous diuretics (using > or = 2 times the usual daily diuretic dose) before using nesiritide. In light of the existing data, we feel that this approach appears to be an appropriate and prudent one for nesiritide's place in therapy.