Abstract:
To survive, animals must constantly balance the need to obtain food with the need to avoid danger. Feeding is essential, yet perceived danger shifts priority toward safety and transiently suppresses food intake, even when organisms are hungry. Hypothalamic pro-opiomelanocortin (POMC) neurons align metabolic outputs with energy demands and control feeding. However, the role of POMC neurons in determining the trade-off between feeding and threat responses remains unclear. Here, fasted mice are exposed to a fear-conditioning paradigm to examine how POMC neurons influence the choice between feeding and defensive behaviors. Behavioral analyses combined with chemogenetic, neuroanatomical, and molecular approaches show that activation of POMC neurons suppresses feeding during a learned threat and it is associated with corticotropin releasing hormone (CRH) neuron-dependent activation of the hypothalamic-pituitary-adrenal (HPA) axis. These effects require cannabinoid type 1 receptor (CB1R) signaling in POMC neurons, uncovering a POMC-CB1R pathway that tunes behavioral flexibility under a perceived threat. Collectively, the data identify POMC neurons as key integrators of metabolic and stress signals that bias decision making between feeding and threat-avoidance behaviors.

Abstract:
Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (G(s)) could rapidly promote the activity of the organelle and possibly compensate for bioenergetic dysfunction. Here, we show that a mitochondria-targeted recombinant designer receptor exclusively activated by designer drugs (mitoDREADD-G(s)) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-G(s) abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer's disease and frontotemporal dementia. Thus, mitoDREADD-G(s) enables the establishment of causal relationships between mitochondria and biological or disease-related processes and represents an innovative potential therapeutic approach for disorders associated with mitochondrial impairment.

Abstract:
The endocannabinoid system (ECS) is a widespread neuromodulatory system involved in both physiological and pathological processes. The ECS has been mainly characterized in neurons, but emerging evidence has revealed its presence in different glial cells. Many studies focused on the functions of the ECS in astrocytes, but its role in other glial cells remains poorly explored. Muller cells are the main glial cells in the retina, providing structural maintenance, metabolic support and neuroprotection to other retinal cells. However, the crosstalk between the ECS and Muller glia (MG) has been scantly described so far. In this context, inspired by similar research on astrocytes, the study of the presence and activity of the ECS in MG is currently emerging as an interesting way of controlling retinal functions in physiopathological conditions. This review will examine the current knowledge on the ECS in MG with the general aim to promote future research in this field.

Abstract:
Neurodegenerative disorders are debilitating conditions that impair patient quality of life and that represent heavy social-economic burdens to society. Whereas the root of some of these brain illnesses lies in autosomal inheritance, the origin of most of these neuropathologies is scantly understood. Similarly, the cellular and molecular substrates explaining the progressive loss of brain functions remains to be fully described too. Indeed, the study of brain neurodegeneration has resulted in a complex picture, composed of a myriad of altered processes that include broken brain bioenergetics, widespread neuroinflammation and aberrant activity of signaling pathways. In this context, several lines of research have shown that the endocannabinoid system (ECS) and its main signaling hub, the type-1 cannabinoid (CB1) receptor are altered in diverse neurodegenerative disorders. However, some of these data are conflictive or poorly described. In this review, we summarize the findings about the alterations in ECS and CB1 receptors signaling in three representative brain illnesses, the Alzheimer's, Parkinson's and Huntington's diseases, and we discuss the relevance of these studies in understanding neurodegeneration development and progression, with a special focus on astrocyte function. Noteworthy, the analysis of ECS defects in neurodegeneration warrant much more studies, as our conceptual understanding of ECS function has evolved quickly in the last years, which now include glia cells and the subcellular-specific CB1 receptors signaling as critical players of brain functions.

Abstract:
Corticosteroid-mediated stress responses require the activation of complex brain circuits involving mitochondrial activity, but the underlying cellular and molecular mechanisms are scantly known. The endocannabinoid system is implicated in stress coping, and it can directly regulate brain mitochondrial functions via type 1 cannabinoid (CB(1)) receptors associated with mitochondrial membranes (mtCB(1)). In this study, we show that the impairing effect of corticosterone in the novel object recognition (NOR) task in mice requires mtCB(1) receptors and the regulation of mitochondrial calcium levels in neurons. Different brain circuits are modulated by this mechanism to mediate the impact of corticosterone during specific phases of the task. Thus, whereas corticosterone recruits mtCB(1) receptors in noradrenergic neurons to impair NOR consolidation, mtCB(1) receptors in local hippocampal GABAergic interneurons are required to inhibit NOR retrieval. These data reveal unforeseen mechanisms mediating the effects of corticosteroids during different phases of NOR, involving mitochondrial calcium alterations in different brain circuits.

Abstract:
The study of the astrocytic contribution to brain functions has been growing in popularity in the neuroscience field. In the last years, and especially since the demonstration of the involvement of astrocytes in synaptic functions, the astrocyte field has revealed multiple functions of these cells that seemed inconceivable not long ago. In parallel, cannabinoid investigation has also identified different ways by which cannabinoids are able to interact with these cells, modify their functions, alter their communication with neurons and impact behavior. In this review, we will describe the expression of different endocannabinoid system members in astrocytes. Moreover, we will relate the latest findings regarding cannabinoid modulation of some of the most relevant astroglial functions, namely calcium (Ca(2+) ) dynamics, gliotransmission, metabolism, and inflammation.

Abstract:
The endocannabinoid system (ECS) is involved in a variety of brain functions, mainly through the activation of the type-1 cannabinoid receptors (CB1R). CB1R are highly expressed throughout the brain at different structural, cellular and subcellular locations and its activity and expression levels have a direct impact in synaptic activity and behavior. In the last few decades, astrocytes have arisen as active players of brain physiology through their participation in the tripartite synapse and through their metabolic interaction with neurons. Here, we discuss some of the mechanisms by which astroglial CB1R at different subcellular locations, regulate astrocyte calcium signals and have an impact on gliotransmission and metabolic regulation. In addition, we discuss evidence pointing at astrocytes as potential important sources of endocannabinoid synthesis and release. Thus, we summarize recent findings that add further complexity and establish that the ECS is a fundamental effector of astrocyte functions in the brain.

Abstract:
Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit Ndufs4, we dissect the critical role of genetically-defined neuronal populations in LS progression. Ndufs4 inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, Ndufs4 deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD.

Abstract:
Systems neuroscience is still mainly a neuronal field, despite the plethora of evidence supporting the fact that astrocytes modulate local neural circuits, networks, and complex behaviors. In this article, we sought to identify which types of studies are necessary to establish whether astrocytes, beyond their well-documented homeostatic and metabolic functions, perform computations implementing mathematical algorithms that sub-serve coding and higher-brain functions. First, we reviewed Systems-like studies that include astrocytes in order to identify computational operations that these cells may perform, using Ca(2+) transients as their encoding language. The analysis suggests that astrocytes may carry out canonical computations in a time scale of subseconds to seconds in sensory processing, neuromodulation, brain state, memory formation, fear, and complex homeostatic reflexes. Next, we propose a list of actions to gain insight into the outstanding question of which variables are encoded by such computations. The application of statistical analyses based on machine learning, such as dimensionality reduction and decoding in the context of complex behaviors, combined with connectomics of astrocyte-neuronal circuits, is, in our view, fundamental undertakings. We also discuss technical and analytical approaches to study neuronal and astrocytic populations simultaneously, and the inclusion of astrocytes in advanced modeling of neural circuits, as well as in theories currently under exploration such as predictive coding and energy-efficient coding. Clarifying the relationship between astrocytic Ca(2+) and brain coding may represent a leap forward toward novel approaches in the study of astrocytes in health and disease.

Abstract:
The prevalent view in neuroenergetics is that glucose is the main brain fuel, with neurons being mostly oxidative and astrocytes glycolytic. Evidence supporting that astrocyte mitochondria are functional has been overlooked. Here we sought to determine what is unique about astrocyte mitochondria by performing unbiased statistical comparisons of the mitochondriome in astrocytes and neurons. Using MitoCarta, a compendium of mitochondrial proteins, together with transcriptomes of mouse neurons and astrocytes, we generated cell-specific databases of nuclear genes encoding for mitochondrion proteins, ranked according to relative expression. Standard and in-house Gene Set Enrichment Analyses (GSEA) of five mouse transcriptomes revealed that genes encoding for enzymes involved in fatty acid oxidation (FAO) and amino acid catabolism are consistently more expressed in astrocytes than in neurons. FAO and oxidative-metabolism-related genes are also up-regulated in human cortical astrocytes versus the whole cortex, and in adult astrocytes versus fetal astrocytes. We thus present the first evidence of FAO in human astrocytes. Further, as shown in vitro, FAO coexists with glycolysis in astrocytes and is inhibited by glutamate. Altogether, these analyses provide arguments against the glucose-centered view of energy metabolism in astrocytes and reveal mitochondria as specialized organelles in these cells.