ABSTRACT
Catecholamine (CA) neurons in the ventrolateral medulla (VLM) contribute importantly to glucoregulation during glucose deficit. However, it is not known which CA neurons elicit different glucoregulatory responses or whether selective activation of CA neurons is sufficient to elicit these responses. Therefore, to selectively activate CA subpopulations, we injected male or female Th-Cre+ transgenic rats with the Cre-dependent DREADD construct, AAV2-DIO-hSyn-hM3D(Gq)-mCherry, at one of four rostrocaudal levels of the VLM: rostral C1 (C1r), middle C1 (C1m), the area of A1 and C1 overlap (A1/C1), and A1. Transfection was highly selective for CA neurons at each site. Systemic injection of the Designer Receptor Exclusively Activated by Designer Drugs (DREADD) receptor agonist, clozapine-N-oxide (CNO), stimulated feeding in rats transfected at C1r, C1m, or A1/C1 but not A1. CNO increased corticosterone secretion in rats transfected at C1m or A1/C1 but not A1. In contrast, CNO did not increase blood glucose or induce c-Fos expression in the spinal cord or adrenal medulla after transfection of any single VLM site but required dual transfection of both C1m and C1r, possibly indicating that CA neurons mediating blood glucose responses are more sparsely distributed in C1r and C1m than those mediating feeding and corticosterone secretion. These results show that selective activation of C1 CA neurons is sufficient to increase feeding, blood glucose levels, and corticosterone secretion and suggest that each of these responses is mediated by CA neurons concentrated at different levels of the C1 cell group.
Subject(s)
Adrenal Medulla/metabolism , Catecholamines/metabolism , Medulla Oblongata/metabolism , Neurons/metabolism , Pharmacogenomic Variants , Receptors, Drug/metabolism , Spinal Cord Lateral Horn/metabolism , Activation, Metabolic , Adrenal Medulla/drug effects , Adrenal Medulla/pathology , Animals , Antipsychotic Agents/adverse effects , Antipsychotic Agents/pharmacokinetics , Behavior, Animal/drug effects , Clozapine/adverse effects , Clozapine/analogs & derivatives , Clozapine/pharmacokinetics , Feeding Behavior/drug effects , Female , Humans , Hyperglycemia/chemically induced , Hyperglycemia/metabolism , Hyperglycemia/pathology , Luminescent Proteins/administration & dosage , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Medulla Oblongata/cytology , Medulla Oblongata/drug effects , Nerve Tissue Proteins/administration & dosage , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Neurons/pathology , Organ Specificity , Rats, Transgenic , Receptors, Drug/administration & dosage , Receptors, Drug/agonists , Receptors, Drug/genetics , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/metabolism , Spinal Cord Lateral Horn/drug effects , Spinal Cord Lateral Horn/pathology , Red Fluorescent ProteinABSTRACT
BACKGROUND AND OBJECTIVE: Loss of intermediolateral nucleus (IML) neurons is considered to play a major role in orthostatic hypotension (OH) of multiple system atrophy (MSA). In Parkinson disease (PD) and dementia with Lewy bodies (DLB), autonomic phenomena such as OH are common and attributed to dysfunction of sympathetic, parasympathetic, and visceral autonomic neurons. However, apart from MSA, few reports have focused on the neuropathologic aspects in PD and DLB. Here we assessed IML degeneration as well as the fine myelinated fibers (FFs; maximum diameter less than 3 µm) considered to be preganglionic sympathetic nerve fibers derived from IML neurons in PD, DLB, MSA, and age-matched normal controls (NC). METHODS: We counted IML neurons and measured the diameter and number of myelinated fibers of the ventral root at the level of the 12th thoracic segment. RESULTS: Compared to NC, number of IML neurons and density of FF were significantly reduced in PD (53% and 67%), DLB (47% and 71%) and MSA (27% and 42%). Compared to combined group of PD and DLB without OH (OH-), IML neurons in combined group of PD and DLB with OH (OH+) were significantly reduced (77%). Compared to NC, FF densities in OH-, OH+ were significantly reduced (74% and 59%). The mean ratio of small to large myelinated fibers in OH+ (1.18), but not that in OH-(1.58), was significantly lower than that in NC (3.17). CONCLUSIONS: We present neuropathological evidence that IML neurons and FFs in the ventral root are reduced in PD and DLB and that the reduction was more severe in the combined group of OH+ than in OH-.
Subject(s)
Lewy Body Disease/pathology , Neurons/pathology , Parkinson Disease/pathology , Spinal Cord Lateral Horn/pathology , Spinal Nerve Roots/pathology , Aged , Aged, 80 and over , Female , Humans , Hypotension, Orthostatic/complications , Hypotension, Orthostatic/pathology , Lewy Body Disease/complications , Male , Nerve Fibers/pathology , Parkinson Disease/complicationsABSTRACT
Structural alterations in the central autonomic nuclei (dorsal vagal complex and intermediolateral nucleus) of the centrifuged random-bred male rats subjected to +Gz loads were examined. Acute exposure to gravitational loads predominantly produced the reactive changes in these nuclei, while persistently repeated regular loads resulted in cumulation of the destructive alterations. The structural perturbations in the central autonomic nuclei can disturb the autonomic regulation of physiological functions. The character of such disturbances is partially determined by the peculiarities in structural organization of these nuclei.
