Hindbrain Administration of Oxytocin Reduces Food Intake, Weight Gain and Activates Catecholamine Neurons in the Hindbrain Nucleus of the Solitary Tract in Rats

Existing studies show that CNS oxytocin (OT) signaling is important in the control of energy balance, but it is unclear which neurons may contribute to these effects. Our goals were to examine (1) the dose-response effects of acute OT administration into the third (3V; forebrain) and fourth (4V; hindbrain) ventricles to assess sensitivity to OT in forebrain and hindbrain sites, (2) the extent to which chronic 4V administration of OT reduces weight gain associated with the progression of diet-induced obesity, and (3) whether nucleus tractus solitarius (NTS) catecholamine neurons are downstream targets of 4V OT. Initially, we examined the dose-response effects of 3V and 4V OT (0.04, 0.2, 1, or 5 μg). 3V and 4V OT (5 μg) suppressed 0.5-h food intake by 71.7 ± 6.0% and 60 ± 12.9%, respectively. 4V OT (0.04, 0.2, 1 μg) reduced food intake by 30.9 ± 12.9, 42.1 ± 9.4, and 56.4 ± 9.0%, respectively, whereas 3V administration of OT (1 μg) was only effective at reducing 0.5-h food intake by 38.3 ± 10.9%. We subsequently found that chronic 4V OT infusion, as with chronic 3V infusion, reduced body weight gain (specific to fat mass) and tended to reduce plasma leptin in high-fat diet (HFD)-fed rats, in part, through a reduction in energy intake. Lastly, we determined that 4V OT increased the number of hindbrain caudal NTS Fos (+) neurons (156 ± 25) relative to vehicle (12 ± 3). The 4V OT also induced Fos in tyrosine hydroxylase (TH; marker of catecholamine neurons) (+) neurons (25 ± 7%) relative to vehicle (0.8 ± 0.3%). Collectively, these findings support the hypothesis that OT within the hindbrain is effective at reducing food intake, weight gain, and adiposity and that NTS catecholamine neurons in addition to non-catecholaminergic neurons are downstream targets of CNS OT.

ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype

Argininosuccinate lyase (ASL) is essential for the NO-dependent regulation of tyrosine hydroxylase (TH) and thus for catecholamine production. Using a conditional mouse model with loss of ASL in catecholamine neurons, we demonstrate that ASL is expressed in dopaminergic neurons in the substantia nigra pars compacta, including the ALDH1A1 + subpopulation that is pivotal for the pathogenesis of Parkinson disease (PD). Neuronal loss of ASL results in catecholamine deficiency, in accumulation and formation of tyrosine aggregates, in elevation of α-synuclein, and phenotypically in motor and cognitive deficits. NO supplementation rescues the formation of aggregates as well as the motor deficiencies. Our data point to a potential metabolic link between accumulations of tyrosine and seeding of pathological aggregates in neurons as initiators for the pathological processes involved in neurodegeneration. Hence, interventions in tyrosine metabolism via regulation of NO levels may be therapeutic beneficial for the treatment of catecholamine-related neurodegenerative disorders.

A ventrolateral medulla-midline thalamic circuit for hypoglycemic feeding

Marked deficits in glucose availability, or glucoprivation, elicit organism-wide counter-regulatory responses whose purpose is to restore glucose homeostasis. However, while catecholamine neurons of the ventrolateral medulla (VLMCA) are thought to orchestrate these responses, the circuit and cellular mechanisms underlying specific counter-regulatory responses are largely unknown. Here, we combined anatomical, imaging, optogenetic and behavioral approaches to interrogate the circuit mechanisms by which VLMCA neurons orchestrate glucoprivation-induced food seeking behavior. Using these approaches, we found that VLMCA neurons form functional connections with nucleus accumbens (NAc)-projecting neurons of the posterior portion of the paraventricular nucleus of the thalamus (pPVT). Importantly, optogenetic manipulations revealed that while activation of VLMCA projections to the pPVT was sufficient to elicit robust feeding behavior in well fed mice, inhibition of VLMCA–pPVT communication significantly impaired glucoprivation-induced feeding while leaving other major counterregulatory responses intact. Collectively our findings identify the VLMCA–pPVT–NAc pathway as a previously-neglected node selectively controlling glucoprivation-induced food seeking. Moreover, by identifying the ventrolateral medulla as a direct source of metabolic information to the midline thalamus, our results support a growing body of literature on the role of the PVT in homeostatic regulation.

Mechanism of Action of Atypical Antipsychotic Drugs in Mood Disorders

Atypical antipsychotic drugs were introduced in the early 1990th. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics show effectiveness against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic, but also in affective disorders, by their own or as adjuncts to antidepressant drugs. While typical antipsychotics act, almost exclusively, via dopamine-2 (D2) receptors, atypical target serotonin-1A/1B/2A/2C (5-HT1A/1B/2A/2C), α1/2-adrenergic, and/or histamine-1 (H1) receptors as well. Blocking of 5-HT1A/1B autoreceptors, inducing their early desensitization, and/or activation of α1-adrenoceptors, allow some atypical drugs to enhance 5-HT transmission. Blocking of 5-HT2A/2C and/or α2-adrenoceptors enable some atypical antipsychotics to stimulate catecholamine transmission and/or diminish the inhibition of catecholamine neurons induced by some antidepressants. It is possible, that the activation of H1 and/or blocking of H3 boost monoamine transmission as well, via a mechanism involving stimulation of firing activity of dopamine neurons. The experimental drugs with antipsychotic potential, acting on adenosine and trace amino associated (TAAR) receptors, might be effective in mood disorders as well, because of the ability to modulate the excitability of monoamine-secreting neurons and to potentiate extracellular concentrations of monoamines in the limbic areas of the brain.

Genetic or toxicant induced disruption of vesicular monoamine storage and global metabolic profiling in Caenorhabditis elegans

The proper storage and release of monoamines contributes to a wide range of neuronal activity. Here, we examine the effects of altered vesicular monoamine transport in the nematode C. elegans. The gene cat-1 is responsible for the encoding of the vesicular monoamine transporter (VMAT) in C. elegans and is analogous to the mammalian vesicular monoamine transporter 2 (VMAT2). Our laboratory has previously shown that reduced VMAT2 activity confers vulnerability on catecholamine neurons in mice. The purpose of this paper was to determine whether this function is conserved and to determine the impact of reduced VMAT activity in C. elegans. Here we show that deletion of cat-1/VMAT increases sensitivity to the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) as measured by enhanced degeneration of dopamine neurons. Reduced cat-1/VMAT also induces changes in dopamine-mediated behaviors. High-resolution mass spectrometry-based metabolomics in the whole organism reveals changes in amino acid metabolism, including tyrosine metabolism in the cat-1/VMAT mutants. Treatment with MPP+ disrupted tryptophan metabolism. Both conditions altered glycerophospholipid metabolism, suggesting a convergent pathway of neuronal dysfunction. Our results demonstrate the evolutionarily conserved nature of monoamine function in C. elegans and further suggest that HRMS-based metabolomics can be used in this model to study environmental and genetic contributors to complex human disease

Thrombin action on astrocytes in the hindbrain of the rat disrupts glycemic and respiratory control

Severe trauma can produce a postinjury “metabolic self-destruction” characterized by catabolic metabolism and hyperglycemia. The severity of the hyperglycemia is highly correlated with posttrauma morbidity and mortality. Although no mechanism has been posited to connect severe trauma with a loss of autonomic control over metabolism, traumatic injury causes other failures of autonomic function, notably, gastric stasis and ulceration (“Cushing’s ulcer”), which has been connected with the generation of thrombin. Our previous studies established that proteinase-activated receptors (PAR1; “thrombin receptors”) located on astrocytes in the autonomically critical nucleus of the solitary tract (NST) can modulate gastric control circuit neurons to cause gastric stasis. Hindbrain astrocytes have also been implicated as important detectors of low glucose or glucose utilization. When activated, these astrocytes communicate with hindbrain catecholamine neurons that, in turn, trigger counterregulatory responses (CRR). There may be a convergence between the effects of thrombin to derange hindbrain gastrointestinal control and the hindbrain circuitry that initiates CRR to increase glycemia in reaction to critical hypoglycemia. Our results suggest that thrombin acts within the NST to increase glycemia through an astrocyte-dependent mechanism. Blockade of purinergic gliotransmission pathways interrupted the effect of thrombin to increase glycemia. Our studies also revealed that thrombin, acting in the NST, produced a rapid, dramatic, and potentially lethal suppression of respiratory rhythm that was also a function of purinergic gliotransmission. These results suggest that the critical connection between traumatic injury and a general collapse of autonomic regulation involves thrombin action on astrocytes.

Corticosterone Upregulates Gene and Protein Expression of Catecholamine Markers in Organotypic Brainstem Cultures

Glucocorticoids are produced by the adrenal cortex and regulate cell metabolism in a variety of organs. This occurs either directly, by acting on specific receptors in a variety of cells, or by stimulating catecholamine expression within neighbor cells of the adrenal medulla. In this way, the whole adrenal gland may support specific metabolic requirements to cope with stressful conditions from external environment or internal organs. In addition, glucocorticoid levels may increase significantly in the presence of inappropriate secretion from adrenal cortex or may be administered at high doses to treat inflammatory disorders. In these conditions, metabolic alterations and increased blood pressure may occur, although altered sleep-waking cycle, anxiety, and mood disorders are frequent. These latter symptoms remain unexplained at the molecular level, although they overlap remarkably with disorders affecting catecholamine nuclei of the brainstem reticular formation. In fact, the present study indicates that various doses of glucocorticoids alter the expression of genes and proteins, which are specific for reticular catecholamine neurons. In detail, corticosterone administration to organotypic mouse brainstem cultures significantly increases Tyrosine hydroxylase (TH) and Dopamine transporter (DAT), while Phenylethanolamine N-methyltransferase (PNMT) is not affected. On the other hand, Dopamine Beta-Hydroxylase (DBH) increases only after very high doses of corticosterone.

Effects of acute and chronic nicotine on catecholamine neurons of the nucleus of the solitary tract

Nicotine is an addictive drug that has broad effects throughout the brain. One site of action is the nucleus of the solitary tract (NTS), where nicotine initiates a stress response and modulates cardiovascular and gastric function through nicotinic acetylcholine receptors (nAChRs). Catecholamine (CA) neurons in the NTS influence stress and gastric and cardiovascular reflexes, making them potential mediators of nicotine’s effects; however nicotine’s effect on these neurons is unknown. Here, we determined nicotine’s actions on NTS-CA neurons by use of patch-clamp techniques in brain slices from transgenic mice expressing enhanced green fluorescent protein driven by the tyrosine hydroxylase promoter (TH-EGFP). Picospritzing nicotine both induced a direct inward current and increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in NTS-CA neurons, effects blocked by nonselective nAChR antagonists TMPH and MLA. The increase in sEPSC frequency was mimicked by nAChRα7 agonist AR-R17779 and blocked by nAChRα7 antagonist MG624. AR-R17779 also increased the firing of TH-EGFP neurons, an effect dependent on glutamate inputs, as it was blocked by the glutamate antagonist NBQX. In contrast, the nicotine-induced current was mimicked by nAChRα4β2 agonist RJR2403 and blocked by nAChRα4β2 antagonist DHβE. RJR2403 also increased the firing rate of TH-EGFP neurons independently of glutamate. Finally, both somatodendritic and sEPSC nicotine responses from NTS-CA neurons were larger in nicotine-dependent mice that had under gone spontaneous nicotine withdrawal. These results demonstrate that 1) nicotine activates NTS-CA neurons both directly, by inducing a direct current, and indirectly, by increasing glutamate inputs, and 2) NTS-CA nicotine responsiveness is altered during nicotine withdrawal.