Both humans and animals seek primary rewards in the environment, even when such rewards do not correspond to current physiological needs. An example of this is a dissociation between food-seeking behaviour and metabolic needs, a notoriously difficult-to-treat symptom of eating disorders. Feeding relies on distinct cell groups in the hypothalamus, the activity of which also changes in anticipation of feeding onset. The hypothalamus receives strong descending inputs from the lateral septum, which is connected, in turn, with cortical networks, but cognitive regulation of feeding-related behaviours is not yet understood. Cortical cognitive processing involves gamma oscillations, which support memory, attention, cognitive flexibility and sensory responses. These functions contribute crucially to feeding behaviour by unknown neural mechanisms. Here we show that coordinated gamma (30-90 Hz) oscillations in the lateral hypothalamus and upstream brain regions organize food-seeking behaviour in mice. Gamma-rhythmic input to the lateral hypothalamus from somatostatin-positive lateral septum cells evokes food approach without affecting food intake. Inhibitory inputs from the lateral septum enable separate signalling by lateral hypothalamus neurons according to their feeding-related activity, making them fire at distinct phases of the gamma oscillation. Upstream, medial prefrontal cortical projections provide gamma-rhythmic inputs to the lateral septum; these inputs are causally associated with improved performance in a food-rewarded learning task. Overall, our work identifies a top-down pathway that uses gamma synchronization to guide the activity of subcortical networks and to regulate feeding behaviour by dynamic reorganization of functional cell groups in the hypothalamus.

A significant number of individuals with type 2 diabetes (T2DM) develop cognitive deficits over time that in some cases could lead to dementia. It remains to be identified the diabetes-related factors or comorbid conditions that drive the association and how they work. In this manuscript, we show that 14-15 month-old hAPP NL/F mice, a knock‐in mouse model of preclinical Alzheimer’s disease (AD) (that is, they generate Aβ42 at an early age but do not show symptoms of the disease until they are old), but not wild type, develop behavioural deficits that correlate with electrophysiological and dendritic spine changes when affected by T2DM. The deficits are not paralleled by higher levels of toxic forms of amyloid beta-peptide (Aβ) or by neuroinflammation but by a reduction in γ-secretase activity, in turn accountable, among other consequences, for a reduction in the levels of the synaptogenesis regulator protein PSD95, and by increased phosphorylation of Tau at epitopes of dendritic spine targeting. RNAseq analysis of the cerebral cortex of wild type and hAPP NL/F, with and without T2DM, revealed the significant downregulation of hypoxia inducible factor 3 (HIF-3α) in the hAPP NL/F diabetic mice only, a decrease that was also observed at the protein level. The main conclusion of this work is that T2DM will trigger or accelerate cognitive illness fundamentally in those individuals who already have a genetic predisposition to AD. A second conclusion is that the cognitive disorders produced by diabetes in these individuals are not due to the excess of toxic forms of Aβ but to other causes, including loss of function of γ-secretase. The third conclusion is that an alteration of the response to hypoxia through Hif3α would be mediating the negative effects of T2DM in the brain.

Hippocampal pyramidal cells encode an animal’s location by single action potentials and complex spike bursts. These elementary signals are believed to play distinct roles in memory consolidation. The timing of single spikes and bursts is determined by intrinsic excitability and theta oscillations (5–10 Hz). Yet contributions of these dynamics to place fields remain elusive due to the lack of methods for specific modification of burst discharge. In mice lacking Kcnq3-containing M-type K+ channels, we find that pyramidal cell bursts are less coordinated by the theta rhythm than in controls during spatial navigation, but not alert immobility. Less modulated bursts are followed by an intact post-burst pause of single spike firing, resulting in a temporal discoordination of network oscillatory and intrinsic excitability. Place fields of single spikes in one- and two-dimensional environments are smaller in the mutant. Optogenetic manipulations of upstream signals reveal that neither medial septal GABA-ergic nor cholinergic inputs alone, but rather their joint activity, is required for entrainment of bursts. Our results suggest that altered representations by bursts and single spikes may contribute to deficits underlying cognitive disabilities associated with KCNQ3-mutations in humans.

In this work, we tested the hypothesis that the development of dementia in individuals with type 2 diabetes (T2DM) requires a genetic background of predisposition to neurodegenerative disease. As a proof of concept, we induced T2DM in middle-aged hAPP NL/F mice, a preclinical model of Alzheimer’s disease. We show that T2DM produces more severe behavioral, electrophysiological, and structural alterations in these mice compared with wild-type mice. Mechanistically, the deficits are not paralleled by higher levels of toxic forms of Aβ or by neuroinflammation but by a reduction in γ-secretase activity, lower levels of synaptic proteins, and by increased phosphorylation of tau. RNA-seq analysis of the cerebral cortex of hAPP NL/F and wild-type mice suggests that the former could be more susceptible to T2DM because of defects in trans-membrane transport. The results of this work, on the one hand, confirm the importance of the genetic background in the severity of the cognitive disorders in individuals with T2DM and, on the other hand, suggest, among the involved mechanisms, the inhibition of γ-secretase activity.

homeostasis del sueño se manifiesta ante situaciones de vigilia prolongada de forma natural o experimentalmente. En estos casos, se presenta somnolencia (o presión de sueño) y, cuando se permite dormir, hay un rebote del sueño en duración e intensidad que compensa la pérdida del mismo. Entre las moléculas que pueden intervenir en la regulación homeostática del sueño, se encuentra la adenosina, cuyos antagonistas, la cafeína y la teofilina, consume la población humana ampliamente como estimulantes. La adenosina es un factor endógeno resultante del metabolismo del ATP en neuronas y glía que se acumula en el medio extracelular y que es capaz de ejercer acciones reguladoras sobre circuitos del ciclo vigilia sueño. Actúa a través de los receptores purinérgicos A 1 y A 2. En este trabajo se presenta una revisión de las vías metabólicas de la adenosina cerebral y de su liberación por neuronas y glía, y se exponen las acciones de la adenosina y de sus antagonistas en regiones del sistema nervioso central de naturaleza hipnogénica y relacionadas con la vigilia. Se exponen, además, los mecanismos sinápticos involucrados en estas acciones. Palabras clave. Acetilcolina. Hipotálamo. Orexinas/hipocretinas. Prosencéfalo basal. Receptores purinérgicos.

No abstract