Diversity of ancestral brainstem noradrenergic neurons across species and multiple biological factors.

The brainstem region, locus coeruleus (LC), has been remarkably conserved across vertebrates. Evolution has woven the LC into wide-ranging neural circuits that influence functions as broad as autonomic systems, the stress response, nociception, sleep, and high-level cognition among others. Given this conservation, there is a strong possibility that LC activity is inherently similar across species, and furthermore that age, sex, and brain state influence LC activity similarly across species.

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 naive 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.

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.

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

Unlabelled: 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.

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.

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-β (Aβ) and tau pathology are both abundant in the forebrain.

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.

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.

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.

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.

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.

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.

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.