Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism.

Agouti-related peptide (AgRP)-expressing and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combine non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP and POMC neurons for comparing metabolic responses in male and female mice with simultaneous activation of AgRP and inhibition of POMC neurons with isolated activation of AgRP neurons or isolated inhibition of POMC neurons. We show that food intake is regulated by the additive effect of AgRP neuron activation and POMC neuron inhibition, while systemic insulin sensitivity and gluconeogenesis are differentially modulated by isolated-versus-simultaneous regulation of AgRP and POMC neurons. We identify a neurocircuit engaging Npy1R-expressing neurons in the paraventricular nucleus of the hypothalamus, where activated AgRP neurons and inhibited POMC neurons cooperate to promote food consumption and activate Th+ neurons in the nucleus tractus solitarii. Collectively, these results unveil how food intake is precisely regulated by the simultaneous bidirectional interplay between AgRP and POMC neurocircuits.

Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting.

Pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus represent key regulators of metabolic homeostasis. Electrophysiological and single-cell sequencing experiments have revealed a remarkable degree of heterogeneity of these neurons. However, the exact molecular basis and functional consequences of this heterogeneity have not yet been addressed. Here, we have developed new mouse models in which intersectional Cre/Dre-dependent recombination allowed for successful labeling, translational profiling and functional characterization of distinct POMC neurons expressing the leptin receptor (Lepr) and glucagon like peptide 1 receptor (Glp1r). Our experiments reveal that POMCLepr+ and POMCGlp1r+ neurons represent largely nonoverlapping subpopulations with distinct basic electrophysiological properties. They exhibit a specific anatomical distribution within the arcuate nucleus and differentially express receptors for energy-state communicating hormones and neurotransmitters. Finally, we identify a differential ability of these subpopulations to suppress feeding. Collectively, we reveal a notably distinct functional microarchitecture of critical metabolism-regulatory neurons.

Motor impairment and compensation in a hemiparkinsonian rat model: correlation between dopamine depletion severity, cerebral metabolism and gait patterns.

BACKGROUND: In Parkinson's disease (PD), cerebral dopamine depletion is associated with PD subtype-specific metabolic patterns of hypo- and hypermetabolism. It has been hypothesised that hypometabolism reflects impairment, while hypermetabolism may indicate compensatory activity. In order to associate metabolic patterns with pathophysiological and compensatory mechanisms, we combined resting state [18F]FDG-PET (to demonstrate brain metabolism in awake animals), [18F]FDOPA-PET (dopamine depletion severity) and gait analysis in a unilateral 6-hydroxydopamine rat model. RESULTS: We found unilateral nigro-striatal dopaminergic loss to decrease swing speed of the contralesional forelimb and stride length of all paws in association with depletion severity. Depletion severity was found to correlate with compensatory changes such as increased stance time of the other three paws and diagonal weight shift to the ipsilesional hind paw. [18F]FDG-PET revealed ipsilesional hypo- and contralesional hypermetabolism; metabolic deactivation of the ipsilesional network needed for sensorimotor integration (hippocampus/retrosplenial cortex/lateral posterior thalamus) was solely associated with bradykinesia, but hypometabolism of the ipsilesional rostral forelimb area was related to both pathological and compensatory gait changes. Mixed effects were also found for hypermetabolism of the contralesional midbrain locomotor region, while contralesional striatal hyperactivation was linked to motor impairments rather than compensation. CONCLUSIONS: Our results indicate that ipsilesional hypo- and contralesional hypermetabolism contribute to both motor impairment and compensation. This is the first time when energy metabolism, dopamine depletion and gait analysis were combined in a hemiparkinsonian model. By experimentally increasing or decreasing compensational brain activity, its potential and limits can be further investigated.

Neural correlates of sensorimotor gating: a metabolic positron emission tomography study in awake rats.

Impaired sensorimotor gating occurs in neuropsychiatric disorders such as schizophrenia and can be measured using the prepulse inhibition (PPI) paradigm of the acoustic startle response. This assay is frequently used to validate animal models of neuropsychiatric disorders and to explore the therapeutic potential of new drugs. The underlying neural network of PPI has been extensively studied with invasive methods and genetic modifications. However, its relevance for healthy untreated animals and the functional interplay between startle- and PPI-related areas during a PPI session is so far unknown. Therefore, we studied awake rats in a PPI paradigm, startle control and background noise control, combined with behavioral [(18)F]fluoro-2-deoxyglucose positron emission tomography (FDG-PET). Subtractive analyses between conditions were used to identify brain regions involved in startle and PPI processing in well-hearing Black hooded rats. For correlative analysis with regard to the amount of PPI we also included hearing-impaired Lister hooded rats that startled more often, because their hearing threshold was just below the lowest prepulses. Metabolic imaging showed that the brain areas proposed for startle and PPI mediation are active during PPI paradigms in healthy untreated rats. More importantly, we show for the first time that the whole PPI modulation network is active during "passive" PPI sessions, where no selective attention to prepulse or startle stimulus is required. We conclude that this reflects ongoing monitoring of stimulus significance and constant adjustment of sensorimotor gating.

Distinct spatiotemporal patterns of spreading depolarizations during early infarct evolution: evidence from real-time imaging.

Experimental and clinical studies indicate that waves of cortical spreading depolarization (CSD) appearing in the ischemic penumbra contribute to secondary lesion growth. We used an embolic stroke model that enabled us to investigate inverse coupling of blood flow by laser speckle imaging (CBF(LSF)) to CSD as a contributing factor to lesion growth already in the early phase after arterial occlusion. Embolization by macrospheres injected into the left carotid artery of anesthetized rats reduced CBF(LSF) in the territories of the middle cerebral artery (MCA) (8/14 animals), the posterior cerebral artery (PCA) (2/14) or in less clearly defined regions (4/14). Analysis of MCA occlusions (MCAOs) revealed a first CSD wave starting off during ischemic decline at the emerging core region, propagating concentrically over large portions of left cortex. Subsequent recurrent waves of CSD did not propagate concentrically but preferentially circled around the ischemic core. In the vicinity of the core region, CSDs were coupled to waves of predominantly vasoconstrictive CBF(LSF) responses, resulting in further decline of CBF in the entire inner penumbra and in expansion of the ischemic core. We conclude that CSDs and corresponding CBF responses follow a defined spatiotemporal order, and contribute to early evolution of ischemic territories.

Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions.

How does infarction in victims of stroke and other types of acute brain injury expand to its definitive size in subsequent days? Spontaneous depolarizations that repeatedly spread across the cerebral cortex, sometimes at remarkably regular intervals, occur in patients with all types of injury. Here, we show experimentally with in vivo real-time imaging that similar, spontaneous depolarizations cycle repeatedly around ischaemic lesions in the cerebral cortex, and enlarge the lesion in step with each cycle. This behaviour results in regular periodicity of depolarization when monitored at a single point in the lesion periphery. We present evidence from clinical monitoring to suggest that depolarizations may cycle in the ischaemic human brain, perhaps explaining progressive growth of infarction. Despite their apparent detrimental role in infarct growth, we argue that cycling of depolarizations around lesions might also initiate upregulation of the neurobiological responses involved in repair and remodelling.