Master of Science / Department of Anatomy and Physiology / Michael J. Kenney / Hyperthermia is an environmental stressor that produces marked increases in visceral sympathetic nerve discharge (SND) in young rats. The brainstem in rats contains the essential neural circuitry for mediating visceral sympathetic activation; however, specific brainstem sites involved remain virtually unknown. The rostral ventral lateral medulla (RVLM) is a key central nervous system region involved in the maintenance of basal SND and in mediating sympathetic nerve responses evoked from supraspinal sites. In the present study we tested the hypothesis that inhibition of RVLM synaptic activation at peak hyperthermia (internal body temperature, Tc, increased to 41.5°C) would affect heating-induced visceral sympathetic activation. Experiments were completed in chloralose-urethane anesthetized, baroreceptor-intact and sinoaortic-denervated, 3-6 month-old Sprague-Dawley rats. Bilateral inhibition of RVLM synaptic activation produced by muscimol microinjections (400 and 800 pmol) at 41.5°C resulted in immediate and significant reductions in peak heating-induced renal and splenic sympathoexcitation. Interruption of RVLM synaptic activation and axonal transmission by lidocaine microinjections (40 nmol) at 41.5°C produced significant reductions in hyperthermia-induced sympathetic activation to similar levels produced by RVLM muscimol microinjections. The total amount of SND inhibited by RVLM muscimol and lidocaine microinjections was significantly more during hyperthermia (41.5°C) than normothermia (38°C). These findings demonstrate that maintenance of sympathetic activation at peak hyperthermia is dependent on the integrity of RVLM neural circuits.

Doctor of Philosophy / Department of Anatomy and Physiology / Michael J. Kenney / It is well established that normal aging is associated with progressive increases in efferent sympathetic nerve discharge (SND). Type II diabetes, obesity, heart failure, and hypertension are pathologies that have been attributed to both the processes of aging and sympathetic dysfunction, exemplifying the importance of understanding central regulation of SND during aging. However, the central mechanisms mediating altered SND with advancing age remain unclear. The rostral ventral lateral medulla (RVLM) is a brainstem region critically involved in setting the basal level of sympathetic outflow and cardiovascular function. Indeed, the RVLM is the only presympathetic region that when bilaterally inactivated results in profound reductions in both SND and arterial pressure. Glutamatergic influences in RVLM activity are powerfully inhibited by tonic GABAergic neural inputs originating from the caudal ventral lateral medulla (CVLM); effects that are mediated by GABAA receptors located on presympathetic neuronal cell bodies within the RVLM. In the present study we proposed that reductions in GABA[subscript A] receptor subunit gene expression may reflect withdrawal of GABAergic tone in the RVLM thereby contributing to the basal sympathetic activation that occurs with advancing age. Therefore, the objective of the current study was to identify age-related changes in the constitutive expression of genes related to GABAergic and muscarinic, nicotinic and dopaminergic receptor systems due to their reported involvement in modulating GABA[subscript A] receptor function, in the RVLM of adult young (3-5 mo. old), middle-aged (12 mo. old), weight stable presenescent (24-25 mo. old) and senescent (>24 mo. old) Fischer 344 (F344) rats using a commercially available real-time PCR array. Real-time analysis revealed nonuniform and age-associated changes in the RVLM GABA, muscarinic, nicotinic and dopaminergic neurotransmitter gene expression profile between young and middle-aged F344 rats. Heterogeneous expression of genes related to these neurotransmitters was also observed between presenescent and senescent F344 rats. Our results suggest that potential changes in neurotransmitter synthesis and degradation, uptake, transport, signaling and receptor subunit composition may account for the sympathoexcitatory state that is commonly observed in the aged.

Ventrolateral medullary neurons have important roles in cardiorespiratory coordination. A rostral extension of the ventral respiratory column (RVRC), including the retrotrapezoid nucleus (RTN), has neurons responsive to local perturbations of CO2 / pH. Respiratory-modulated firing patterns of RVRC neurons are attributed to influences of more caudal (CVRC) neurons. These circuits remain poorly understood. This study addressed the hypothesis that both local interactions and influences from the CVRC shape rostral neuron discharge patterns and responses. Spike trains from 294 rostral and 490 caudal neurons were recorded with multi-electrode arrays along with phrenic nerve activity in 14 decerebrate, vagotomized cats. Overall, 214 rostral and 398 caudal neurons were respiratory-modulated; 124 and 95, respectively, were cardiac-modulated. Subsets of these neurons were evaluated for responses to sequential, selective, transient stimulation of central and peripheral chemoreceptors and arterial baroreceptors. In 5 experiments, Mayer wave-related oscillations (MWROs) in neuronal firing rates were evoked, enhanced, or reduced following central chemoreceptor stimulation. Overall, 174 of the rostral neurons (59.5%) had short- time scale correlations with other RVRC neurons. Of these, 49 triggered cross-correlograms with RVRC targets yielding 330 offset features indicative of paucisynaptic actions from a total of 2,884 rostral pairs evaluated. Forty-nine of the CVRC neurons (10.0%) were triggers in 142 CVRC-RVRC correlograms - from a total of 8,490 - with offset features indicative of actions on RVRC neurons. Correlation linkage maps support the hypothesis that local circuit mechanisms contribute to the respiratory and cardiac modulation of RVRC neurons and their responses to chemoreceptor and baroreceptor challenges.