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The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Aβ plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versus sleep and ~100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

The nucleus of the solitary tract (NTS) receives visceral information and regulates appetitive, digestive, and cardiorespiratory systems. Within the NTS, diverse processes operate in parallel to sustain life, but our understanding of their cellular composition is incomplete. Here, we integrate histologic and transcriptomic analysis to identify and compare molecular features that distinguish neurons in this brain region. Most glutamatergic neurons in the NTS and area postrema co‐express the transcription factors Lmx1b and Phox2b, except for a ventral band of neurons in the far‐caudal NTS, which include the Gcg‐expressing neurons that produce glucagon‐like peptide 1 (GLP‐1). GABAergic interneurons intermingle through the Lmx1b+Phox2b macropopulation, and dense clusters of GABAergic neurons surround the NTS. The Lmx1b+Phox2b macropopulation includes subpopulations with distinct distributions expressing Grp, Hsd11b2, Npff, Pdyn, Pou3f1, Sctr, Th, and other markers. These findings highlight Lmx1b–Phox2b co‐expression as a common feature of glutamatergic neurons in the NTS and improve our understanding of the organization and distribution of neurons in this critical brain region. [ABSTRACT FROM AUTHOR]

In the brain, connectivity determines function. Neurons in the parabrachial nucleus (PB) relay diverse information to widespread brain regions, but the connections and functions of PB neurons that express Nps (neuropeptide S, NPS) remain mysterious. Here, we use Cre‐dependent anterograde tracing and whole‐brain analysis to map their output connections. While many other PB neurons project ascending axons through the central tegmental tract, NPS axons reach the forebrain via distinct periventricular and ventral pathways. Along the periventricular pathway, NPS axons target the tectal longitudinal column and periaqueductal gray, then continue rostrally to target the paraventricular nucleus of the thalamus. Along the ventral pathway, NPS axons blanket much of the hypothalamus but avoid the ventromedial and mammillary nuclei. They also project prominently to the ventral bed nucleus of the stria terminalis, A13 cell group, and magnocellular subparafasciular nucleus. In the hindbrain, NPS axons have fewer descending projections, targeting primarily the superior salivatory nucleus, nucleus of the lateral lemniscus, and periolivary region. Combined with what is known already about NPS and its receptor, the output pattern of Nps‐expressing neurons in the PB region predicts roles in threat response and circadian behavior. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in DLB and PDD. Objective: To investigate the long-term behavioral and cognitive consequences of α-syn pathology in the cortex and characterize pathological spread of α-syn. Methods: We injected human α-syn pre-formed fibrils into the PFC of wild-type male mice. We then assessed the behavioral and cognitive effects between 12- and 21-months post-injection and characterized the spread of pathological α-syn in cortical, subcortical, and brainstem regions. Results: We report that PFC PFFs: 1) induced α-syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; and 3) increased open field exploration. Conclusions: This model of cortical-dominant pathology aids in our understanding of how local α-syn aggregation might impact some symptoms in PDD and DLB. [ABSTRACT FROM AUTHOR]

Pharmacological and physiological phenomena suggest that cells somewhere inside the central nervous system are responsive to aldosterone. Here, we present the fundamental physiological limitations for aldosterone action in the brain, including its limited blood-brain barrier penetration and its substantial competition from glucocorticoids. Recently, a small group of neurons with unusual sensitivity to circulating aldosterone were identified in the nucleus of the solitary tract. We review the discovery and characterization of these neurons, which express the enzyme 11[beta]-hydroxysteroid dehydrogenase type 2, and consider alternative proposals regarding sites and mechanisms for mineralocorticoid action within the brain. sodium deficiency; glucocorticoids; mineralocorticoids; nucleus of the solitary tract; blood-brain barrier; 11[beta]-hydroxysteroid dehydrogenase

Thirst and sodium appetite are both critical for restoring blood volume. Because these two behavioral drives can arise under similar physiological conditions, some of the brain sensory sites that stimulate thirst may also drive sodium appetite. However, the physiological and temporal dynamics of these two appetites exhibit clear differences, suggesting that they involve separate brain circuits. Unlike thirst-associated sensory neurons in the hypothalamus, the 11-[beta]-hydroxysteroid dehydrogenase type 2 (HSD2) neurons in the rat nucleus tractus solitarius (NTS) are activated in close association with sodium appetite (16). Here, we tested whether the HSD2 neurons are also activated in response to either of the two physiological stimuli for thirst: hyperosmolarity and hypovolemia. Hyperosmolarity, produced by intraperitoneal injection of hypertonic saline, stimulated a large increase in water intake and a substantial increase in immunoreactivity for the neuronal activity marker c-Fos within the medial NTS, but not in the HSD2 neurons. Hypovolemia, produced by subcutaneous injection of hyperoncotic polyethylene glycol (PEG), stimulated an increase in water intake within 1-4 h without elevating c-Fos expression in the HSD2 neurons. The HSD2 neurons were, however, activated by prolonged hypovolemia, which also stimulated sodium appetite. Twelve hours after PEG was injected in rats that had been sodium deprived for 4 days, the HSD2 neurons showed a consistent increase in c-Fos immunoreactivity. In summary, the HSD2 neurons are activated specifically in association with sodium appetite and appear not to function in thirst. salt appetite; fluid ingestion; hypovolemia; mineralocorticoid: nucleus of the solitary tract