Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodents.

OBJECTIVE: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain-SNS-adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver. METHODS: We examined the role of lipolysis, and the brain-SNS-adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1ß (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with ß3 adrenergic agonist or undergoing restraint stress. RESULTS: Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through ß3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis. CONCLUSIONS: Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD.

Norepinephrine release in the cerebellum contributes to aversive learning.

The modulation of dopamine release from midbrain projections to the striatum has long been demonstrated in reward-based learning, but the synaptic basis of aversive learning is far less characterized. The cerebellum receives axonal projections from the locus coeruleus, and norepinephrine release is implicated in states of arousal and stress, but whether aversive learning relies on plastic changes in norepinephrine release in the cerebellum is unknown. Here we report that in mice, norepinephrine is released in the cerebellum following an unpredicted noxious event (a foot-shock) and that this norepinephrine release is potentiated powerfully with fear acquisition as animals learn that a previously neutral stimulus (tone) predicts the aversive event. Importantly, both chemogenetic and optogenetic inhibition of the locus coeruleus-cerebellum pathway block fear memory without impairing motor function. Thus, norepinephrine release in the cerebellum is modulated by experience and underlies aversive learning.

Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain.

Dysregulated inflammation within the central nervous system (CNS) contributes to neuropathology in infectious, autoimmune, and neurodegenerative disease. With the exception of microglia, major histocompatibility complex (MHC) proteins are virtually undetectable in the mature, healthy central nervous system (CNS). Neurons have generally been considered incapable of antigen presentation, and although interferon gamma (IFN-γ) can elicit neuronal MHC class I (MHC-I) expression and antigen presentation in vitro, it has been unclear whether similar responses occur in vivo. Here we directly injected IFN-γ into the ventral midbrain of mature mice and analyzed gene expression profiles of specific CNS cell types. We found that IFN-γ upregulated MHC-I and associated mRNAs in ventral midbrain microglia, astrocytes, oligodendrocytes, and GABAergic, glutamatergic, and dopaminergic neurons. The core set of IFN-γ-induced genes and their response kinetics were similar in neurons and glia, but with a lower amplitude of expression in neurons. A diverse repertoire of genes was upregulated in glia, particularly microglia, which were the only cells to undergo cellular proliferation and express MHC classII (MHC-II) and associated genes. To determine if neurons respond directly via cell-autonomous IFN-γ receptor (IFNGR) signaling, we produced mutant mice with a deletion of the IFN-γ-binding domain of IFNGR1 in dopaminergic neurons, which resulted in a complete loss of dopaminergic neuronal responses to IFN-γ. Our results demonstrate that IFN-γ induces neuronal IFNGR signaling and upregulation of MHC-I and related genes in vivo, although the expression level is low compared to oligodendrocytes, astrocytes, and microglia.

Interpreting the role of the striatum during multiple phases of motor learning.

The synaptic pathways in the striatum are central to basal ganglia functions including motor control, learning and organization, action selection, acquisition of motor skills, cognitive function, and emotion. Here, we review the role of the striatum and its connections in motor learning and performance. The development of new techniques to record neuronal activity and animal models of motor disorders using neurotoxin, pharmacological, and genetic manipulations are revealing pathways that underlie motor performance and motor learning, as well as how they are altered by pathophysiological mechanisms. We discuss approaches that can be used to analyze complex motor skills, particularly in rodents, and identify specific questions central to understanding how striatal circuits mediate motor learning.

Roles for the Dorsal Striatum in Aversive Behavior.

The ability to identify and avoid environmental stimuli that signal danger is essential to survival. Our understanding of how the brain encodes aversive behaviors has been primarily focused on roles for the amygdala, hippocampus (HIPP), prefrontal cortex, ventral midbrain, and ventral striatum. Relatively little attention has been paid to contributions from the dorsal striatum (DS) to aversive learning, despite its well-established role in stimulus-response learning. Here, we review studies exploring the role of DS in aversive learning, including different roles for the dorsomedial and dorsolateral striatum in Pavlovian fear conditioning as well as innate and inhibitory avoidance (IA) behaviors. We outline how future investigation might determine specific contributions from DS subregions, cell types, and connections that contribute to aversive behavior.

Role of ß3-adrenergic receptor in the modulation of synaptic transmission and plasticity in mouse cerebellar cortex.

Convergent lines of evidence have recently highlighted ß3-adrenoreceptors (ARs) as a potentially critical target in the regulation of nervous and behavioral functions, including memory consolidation, anxiety, and depression. Nevertheless, the role of ß3-ARs in the cerebellum has been never investigated. To address this issue, we first examined the effects of pharmacological manipulation of ß3-ARs on motor learning in mice. We found that blockade of ß3-ARs by SR 59230A impaired the acquisition of the rotarod task with no effect on general locomotion. Since the parallel fiber-Purkinje cell (PF-PC) synapse is considered to be the main cerebellar locus of motor learning, we assessed ß3-AR modulatory action on this synapse as well as its expression in cerebellar slices. We demonstrate, for the first time, a strong expression of ß3-ARs on Purkinje cell soma and dendrites. In addition, whole-cell patch-clamp recordings revealed that bath application of ß3-AR agonist CL316,243 depressed the PF-PC excitatory postsynaptic currents via a postsynaptic mechanism mediated by the PI3K signaling pathway. Application of CL316,243 also interfered with the expression of PF long-term potentiation, whereas SR 59230A prevented the induction of LTD at PF-PC synapse. These results underline the critical role of ß3-AR on cerebellar synaptic transmission and plasticity and provide a new mechanism for adrenergic modulation of motor learning.