Descending pathways from the superior colliculus mediating autonomic and respiratory effects associated with orienting behaviour.

The ability to discriminate competing external stimuli and initiate contextually appropriate behaviours is a key brain function. Neurons in the deep superior colliculus (dSC) integrate multisensory inputs and activate descending projections to premotor pathways responsible for orienting, attention and defence, behaviours which involve adjustments to respiratory and cardiovascular parameters. However, the neural pathways that subserve the physiological components of orienting are poorly understood. We report that orienting responses to optogenetic dSC stimulation are accompanied by short-latency autonomic, respiratory and electroencephalographic effects in awake rats, closely mimicking those evoked by naturalistic alerting stimuli. Physiological responses were not accompanied by detectable aversion or fear, and persisted under urethane anaesthesia, indicating independence from emotional stress. Anterograde and trans-synaptic viral tracing identified a monosynaptic pathway that links the dSC to spinally projecting neurons in the medullary gigantocellular reticular nucleus (GiA), a key hub for the coordination of orienting and locomotor behaviours. In urethane-anaesthetized animals, sympathoexcitatory and cardiovascular, but not respiratory, responses to dSC stimulation were replicated by optogenetic stimulation of the dSC-GiA terminals, suggesting a likely role for this pathway in mediating the autonomic components of dSC-mediated responses. Similarly, extracellular recordings from putative GiA sympathetic premotor neurons confirmed short-latency excitatory inputs from the dSC. This pathway represents a likely substrate for autonomic components of orienting responses that are mediated by dSC neurons and suggests a mechanism through which physiological and motor components of orienting behaviours may be integrated without the involvement of higher centres that mediate affective components of defensive responses. KEY POINTS: Neurons in the deep superior colliculus (dSC) integrate multimodal sensory signals to elicit context-dependent innate behaviours that are accompanied by stereotypical cardiovascular and respiratory activities. The pathways responsible for mediating the physiological components of colliculus-mediated orienting behaviours are unknown. We show that optogenetic dSC stimulation evokes transient orienting, respiratory and autonomic effects in awake rats which persist under urethane anaesthesia. Anterograde tracing from the dSC identified projections to spinally projecting neurons in the medullary gigantocellular reticular nucleus (GiA). Stimulation of this pathway recapitulated autonomic effects evoked by stimulation of dSC neurons. Electrophysiological recordings from putative GiA sympathetic premotor neurons confirmed short latency excitatory input from dSC neurons. This disynaptic dSC-GiA-spinal sympathoexcitatory pathway may underlie autonomic adjustments to salient environmental cues independent of input from higher centres.

Resetting of the Baroreflex Control of Sympathetic Vasomotor Activity during Natural Behaviors: Description and Conceptual Model of Central Mechanisms.

The baroreceptor reflex controls arterial pressure primarily via reflex changes in vascular resistance, rather than cardiac output. The vascular resistance in turn is dependent upon the activity of sympathetic vasomotor nerves innervating arterioles in different vascular beds. In this review, the major theme is that the baroreflex control of sympathetic vasomotor activity is not constant, but varies according to the behavioral state of the animal. In contrast to the view that was generally accepted up until the 1980s, I argue that the baroreflex control of sympathetic vasomotor activity is not inhibited or overridden during behaviors such as mental stress or exercise, but instead is reset under those conditions so that it continues to be highly effective in regulating sympathetic activity and arterial blood pressure at levels that are appropriate for the particular ongoing behavior. A major challenge is to identify the central mechanisms and neural pathways that subserve such resetting in different states. A model is proposed that is capable of simulating the different ways in which baroreflex resetting is occurred. Future studies are required to determine whether this proposed model is an accurate representation of the central mechanisms responsible for baroreflex resetting.

Central neural control of the cardiovascular system: current perspectives.

This brief review, which is based on a lecture presented at the American Physiological Society Teaching Refresher Course on the Brain and Systems Control as part of the Experimental Biology meeting in 2015, aims to summarize current concepts of the principal mechanisms in the brain that regulate the autonomic outflow to the cardiovascular system. Such cardiovascular regulatory mechanisms do not operate in isolation but are closely coordinated with respiratory and other regulatory mechanisms to maintain homeostasis. The brain regulates the cardiovascular system by two general means: 1) feedforward regulation, often referred to as "central command," and 2) feedback or reflex regulation. In most situations (e.g., during exercise, defensive behavior, sleep, etc.), both of these general mechanisms contribute to overall cardiovascular homeostasis. The review first describes the mechanisms and central circuitry subserving the baroreceptor, chemoreceptor, and other reflexes that work together to regulate an appropriate level of blood pressure and blood oxygenation and then considers the brain mechanisms that defend the body against more complex environmental challenges, using dehydration and cold and heat stress as examples. The last section of the review considers the central mechanisms regulating cardiovascular function associated with different behaviors, with a specific focus on defensive behavior and exercise.

Brain-heart interactions: physiology and clinical implications.

The brain controls the heart directly through the sympathetic and parasympathetic branches of the autonomic nervous system, which consists of multi-synaptic pathways from myocardial cells back to peripheral ganglionic neurons and further to central preganglionic and premotor neurons. Cardiac function can be profoundly altered by the reflex activation of cardiac autonomic nerves in response to inputs from baro-, chemo-, nasopharyngeal and other receptors as well as by central autonomic commands, including those associated with stress, physical activity, arousal and sleep. In the clinical setting, slowly progressive autonomic failure frequently results from neurodegenerative disorders, whereas autonomic hyperactivity may result from vascular, inflammatory or traumatic lesions of the autonomic nervous system, adverse effects of drugs and chronic neurological disorders. Both acute and chronic manifestations of an imbalanced brain-heart interaction have a negative impact on health. Simple, widely available and reliable cardiovascular markers of the sympathetic tone and of the sympathetic-parasympathetic balance are lacking. A deeper understanding of the connections between autonomic cardiac control and brain dynamics through advanced signal and neuroimage processing may lead to invaluable tools for the early detection and treatment of pathological changes in the brain-heart interaction.

Coordinated autonomic and respiratory responses evoked by alerting stimuli: Role of the midbrain colliculi.

Threatening stimuli trigger rapid and coordinated behavioral responses supported by cardiorespiratory changes. The midbrain colliculi can generate coordinated orienting or defensive behavioral responses, and it has been proposed that collicular neurons also generate appropriate cardiovascular and respiratory responses to support such behaviors. We have shown previously that under conditions where collicular neurons are disinhibited, coordinated cardiovascular, somatomotor and respiratory responses can be evoked independently of the cortex by auditory, visual and somatosensory stimuli. Here we report that these natural stimuli effectively increase inspiratory time most likely though phase switching. As a result the pattern of phrenic and sympathetic coupling is an inspiratory-related sympathoexcitation. We propose that blockade of tonic GABAergic input in the midbrain colliculi permits alerting stimuli to drive command neurons that generate coordinated cardiovascular, respiratory and motor outputs. The outputs of these command neurons likely interact with the central respiratory pattern generator, however the precise output pathways mediating the coordinated autonomic and respiratory responses remain to be determined.

Both Ox1R and Ox2R orexin receptors contribute to the cardiorespiratory response evoked from the perifornical hypothalamus.

Orexin/hypocretin neurons are located in and around the perifornical hypothalamus. Disinhibition of this area in the anaesthetized preparation evokes cardiorespiratory changes that can be reduced to nearly half or more by systemic Almorexant, a dual receptor antagonist of the two known orexin receptors, Ox1R and Ox2R. It is not clear if these reductions result from the blockade of one receptor or both. To determine the contribution of the two receptors, we compared the effects of Almorexant to those of the selective Ox1R antagonist ACT335827 and the selective Ox2R antagonists EMPA and TCS-OX2-29. Bicuculline (20 pmol) was injected in the perifornical hypothalamus of urethane-anaesthetized rats before and after administration of the drugs (all 15 mg/kg, intravenously). The pressor, tachycardic and tachypneic responses to bicuculline were attenuated/reduced by ACT335827 (by 19%, ns; 10%, ns and 24%, P < 0.01, respectively), EMPA (by 35% P < 0.01; 6%, ns; and 26% P < 0.05) and TCS-OX2-29 (by 13%, ns; 10%, ns and 42%, P < 0.001). These reductions represented only a fraction of the reduction after Almorexant (by 43%, P < 0.001; 42%, P < 0.001 and 65% P < 0.001). However, when the selective Ox1R and Ox2R antagonists were given in combination, the reductions were greater and closer to those of Almorexant (ACT335827 + EMPA, by 26%, P < 0.05; 24%, P < 0.05 and 47%, P < 0.001; ACT335827 + TCS-OX2-29, by 40%, P < 0.01; 26%, P < 0.001 and 59%, P < 0.0001). This was particularly clear with the tachypneic response. These results suggest that both orexin receptors contribute to the cardiorespiratory response evoked from the hypothalamus under anaesthesia. They are consistent with our previous study in the conscious animal.

Central mechanisms regulating coordinated cardiovascular and respiratory function during stress and arousal.

Actual or potentially threatening stimuli in the external environment (i.e., psychological stressors) trigger highly coordinated defensive behavioral responses that are accompanied by appropriate autonomic and respiratory changes. As discussed in this review, several brain regions and pathways have major roles in subserving the cardiovascular and respiratory responses to threatening stimuli, which may vary from relatively mild acute arousing stimuli to more prolonged life-threatening stimuli. One key region is the dorsomedial hypothalamus, which receives inputs from the cortex, amygdala, and other forebrain regions and which is critical for generating autonomic, respiratory, and neuroendocrine responses to psychological stressors. Recent studies suggest that the dorsomedial hypothalamus also receives an input from the dorsolateral column in the midbrain periaqueductal gray, which is another key region involved in the integration of stress-evoked cardiorespiratory responses. In addition, it has recently been shown that neurons in the midbrain colliculi can generate highly synchronized autonomic, respiratory, and somatomotor responses to visual, auditory, and somatosensory inputs. These collicular neurons may be part of a subcortical defense system that also includes the basal ganglia and which is well adapted to responding to threats that require an immediate stereotyped response that does not involve the cortex. The basal ganglia/colliculi system is phylogenetically ancient. In contrast, the defense system that includes the dorsomedial hypothalamus and cortex evolved at a later time, and appears to be better adapted to generating appropriate responses to more sustained threatening stimuli that involve cognitive appraisal.

Bidirectional interactions between the baroreceptor reflex and arousal: an update.

Studies involving genetic engineering on animal models and mathematical analysis of cardiovascular signals on humans are shedding new light on the interactions between the arterial baroreceptor reflex (baroreflex) and arousal. Baroreceptor stimulation, if very mild or performed under anaesthesia, may inhibit cortical arousal. However, substantial increases or decreases in baroreflex activation cause arousal in animal models and human subjects in physiological conditions. On the other hand, cardiovascular changes during autonomic arousals and between the states of wakefulness and sleep involve changes in the baroreflex set point and balance with central autonomic commands. Neural connectivity and functional data suggest that the nucleus of the solitary tract, adrenergic C1 neurons of the medulla, and the parabrachial nucleus of the pons mediate the bidirectional interactions between the baroreflex and arousal. These interactions may constitute a positive feedback loop that facilitates sharp and coordinated brain state and autonomic transitions upon arousal: upon arousal, central autonomic commands may increase blood pressure, thereby loading baroreceptors and further increasing arousal. Anomalies of this feedback loop may play a role in the pathophysiology of disease conditions associated with cardiovascular and sleep-wake cycle alterations. These conditions include: obstructive sleep apnoea syndrome, with its association with excessive daytime sleepiness and baroreflex impairment; and insomnia, with its association with autonomic hyperarousal and hypertension. When faced with disorders associated with cardiovascular and sleep-wake cycle alterations, clinical reasoning should entertain the possibility that both conditions are strongly influenced by anomalies of baroreflex function.

Disinhibition of the midbrain colliculi unmasks coordinated autonomic, respiratory, and somatomotor responses to auditory and visual stimuli.

The midbrain superior and inferior colliculi have critical roles in generating coordinated orienting or defensive behavioral responses to environmental stimuli, and it has been proposed that neurons within the colliculi can also generate appropriate cardiovascular and respiratory responses to support such behavioral responses. We have previously shown that activation of neurons within a circumscribed region in the deep layers of the superior colliculus and in the central and external nuclei of the inferior colliculus can evoke a response characterized by intense and highly synchronized bursts of renal sympathetic nerve activity and phrenic nerve activity. In this study, we tested the hypothesis that, under conditions in which collicular neurons are disinhibited, coordinated cardiovascular, somatomotor, and respiratory responses can be evoked by natural environmental stimuli. In response to natural auditory, visual, or somatosensory stimuli, powerful synchronized increases in sympathetic, respiratory, and somatomotor activity were generated following blockade of GABAA receptors in a specific region in the midbrain colliculi of anesthetized rats, but not under control conditions. Such responses still occurred after removal of most of the forebrain, including the amygdala and hypothalamus, indicating that the essential pathways mediating these coordinated responses were located within the brain stem. The temporal relationships between the different outputs suggest that they are driven by a common population of "command neurons" within the colliculi.

The effect of air puff stress on c-Fos expression in rat hypothalamus and brainstem: central circuitry mediating sympathoexcitation and baroreflex resetting.

Psychological stress evokes increases in sympathetic activity and blood pressure, which are due at least in part to an upward resetting of the baroreceptor-sympathetic reflex. In this study we determined whether sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM), which have a critical role in the reflex control of sympathetic activity, are activated during air puff stress, a moderate psychological stressor. Secondly, we identified neurons that are activated by air puff stress and that also project to the nucleus tractus solitarius (NTS), a key site for modulation of the baroreceptor reflex. Air puff stress resulted in increased c-Fos expression in several hypothalamic and brainstem nuclei, including the paraventricular nucleus (PVN), dorsomedial hypothalamus, perifornical area (PeF), periaqueductal gray (PAG), NTS and rostral ventromedial medulla, but not in the RVLM region that contains sympathetic premotor neurons. In contrast, neurons in this RVLM region, including catecholamine-synthesizing neurons, did express c-Fos following induced hypotension, which reflexly activates RVLM sympathetic premotor neurons. The highest proportion of NTS-projecting neurons that were double-labelled with c-Fos after air puff stress was in the ventrolateral PAG (29.3 ± 5.5%), with smaller but still significant proportions of double-labelled NTS-projecting neurons in the PVN and PeF (6.5 ± 1.8 and 6.4 ± 1.7%, respectively). The results suggest that the increased sympathetic activity during psychological stress is not driven primarily by RVLM sympathetic premotor neurons, and that neurons in the PVN, PeF and ventrolateral PAG may contribute to the resetting of the baroreceptor-sympathetic reflex that is associated with psychological stress.

Central control of cardiovascular function during sleep.

There is increasing evidence that cardiovascular control during sleep is relevant for cardiovascular risk. This evidence warrants increased experimental efforts to understand the physiological mechanisms of such control. This review summarizes current knowledge on autonomic features of sleep states [non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS)] and proposes some testable hypotheses concerning the underlying neural circuits. The physiological reduction of blood pressure (BP) during the night (BP dipping phenomenon) is mainly caused by generalized cardiovascular deactivation and baroreflex resetting during NREMS, which, in turn, are primarily a consequence of central autonomic commands. Central commands during NREMS may involve the hypothalamic ventrolateral preoptic area, central thermoregulatory and central baroreflex pathways, and command neurons in the pons and midbrain. During REMS, opposing changes in vascular resistance in different regional beds have the net effect of increasing BP compared with that of NREMS. In addition, there are transient increases in BP and baroreflex suppression associated with bursts of brain and skeletal muscle activity during REMS. These effects are also primarily a consequence of central autonomic commands, which may involve the midbrain periaqueductal gray, the sublaterodorsal and peduncular pontine nuclei, and the vestibular and raphe obscurus medullary nuclei. A key role in permitting physiological changes in BP during sleep may be played by orexin peptides released by hypothalamic neurons, which target the postulated neural pathways of central autonomic commands during NREMS and REMS. Experimental verification of these hypotheses may help reveal which central neural pathways and mechanisms are most essential for sleep-related changes in cardiovascular function.

Role of dorsolateral periaqueductal grey in the coordinated regulation of cardiovascular and respiratory function.

The midbrain periaqueductal grey (PAG) contains four longitudinal columns, referred to as the dorsomedial (dmPAG), dorsolateral (dlPAG), lateral (lPAG) and ventrolateral (vlPAG) subdivisions, which collectively have a pivotal role in integrating behavioural and physiological responses to external stressors as well as other functions. This review is focussed on the dlPAG, which is believed to be an important component of the central mechanisms that generate the defensive response to acute psychological stressors, such as the presence of a predator or other immediate threat. The anatomical connections of the dlPAG are highly specific and distinctly different from those of the other PAG subregions. The chemical properties of the dlPAG are also distinctly different from the other PAG subregions (e.g. there is a very high density of neurons that synthesize nitric oxide in the dlPAG but very few such neurons in the other PAG subregions). Recent functional studies have demonstrated that neurons in the dlPAG exert a powerful control over both sympathetic and respiratory activity, and that the pattern of the evoked respiratory changes is also distinctly different from those evoked from other PAG subregions. These studies also showed that the sympathetic and respiratory changes evoked from the dlPAG are highly correlated, suggesting the possibility that a common population of "command neurons" within this region may generate the sympathetic and respiratory changes that accompany defensive behavioural responses to acute psychological stressors. Finally, although the anatomical connections and functional properties of the dlPAG are distinctly different from the other PAG subregions, they have many similarities with adjacent parts of the superior colliculus, suggesting that the dlPAG and deep layers of the superior colliculus may be part of a common defence system in the midbrain.

Blockade of orexin receptors with Almorexant reduces cardiorespiratory responses evoked from the hypothalamus but not baro- or chemoreceptor reflex responses.

Orexin neurons form a restricted group in the dorsal hypothalamus. The group is centered on the perifornical area within the classic hypothalamic defense area, an area which when activated produces marked cardiovascular and respiratory effects. Central administration of orexin can produce cardiorespiratory effects, but the extent to which orexin contributes to such responses evoked from the perifornical hypothalamus is not clear. To determine this, we used the dual orexin receptor antagonist Almorexant to challenge the cardiorespiratory effects evoked by disinhibition of the perifornical hypothalamus. Bicuculline (10 and 20 pmol) was microinjected in the perifornical area before and after administration of Almorexant (15 mg/kg iv) or vehicle in urethane-anesthetized rats. Almorexant significantly reduced the pressor, tachycardic, renal sympathoexcitatory, and tachypneic responses to bicuculline (10 pmol, by 55%, 53%, 28%, 77%; 20 pmol, by 54%, 27%, 51%, 72%, respectively). Reductions of similar magnitude were observed with bicuculline microinjections centered on more caudal sites just peripheral to the orexin neuron group, which would likely have activated fewer orexin neurons. In contrast, Almorexant had no effect on the cardiorespiratory response of the chemoreflex (sodium cyanide injection) or the sympathetic component of the baroreflex. Thus orexin makes a major contribution to the cardiorespiratory response evoked from the perifornical area even though orexin neurons represent only a fraction of the output of this area. Orexin neurons may also mediate cardiorespiratory responses from non-orexin neurons in the caudal hypothalamus. However, under resting conditions, blockade of orexin receptors does not affect the chemo- and baroreflexes.

Synchronized activation of sympathetic vasomotor, cardiac, and respiratory outputs by neurons in the midbrain colliculi.

The superior and inferior colliculi are believed to generate immediate and highly coordinated defensive behavioral responses to threatening visual and auditory stimuli. Activation of neurons in the superior and inferior colliculi have been shown to evoke increases in cardiovascular and respiratory activity, which may be components of more generalized stereotyped behavioral responses. In this study, we examined the possibility that there are "command neurons" within the colliculi that can simultaneously drive sympathetic and respiratory outputs. In anesthetized rats, microinjections of bicuculline (a GABA(A) receptor antagonist) into sites within a circumscribed region in the deep layers of the superior colliculus and in the central and external nuclei of the inferior colliculus evoked a response characterized by intense and highly synchronized bursts of renal sympathetic nerve activity (RSNA) and phrenic nerve activity (PNA). Each burst of RSNA had a duration of ∼300-400 ms and occurred slightly later (peak to peak latency of 41 ± 8 ms) than the corresponding burst of PNA. The bursts of RSNA and PNA were also accompanied by transient increases in arterial pressure and, in most cases, heart rate. Synchronized bursts of RSNA and PNA were also evoked after neuromuscular blockade, artificial ventilation, and vagotomy and so were not dependent on afferent feedback from the lungs. We propose that the synchronized sympathetic-respiratory responses are driven by a common population of neurons, which may normally be activated by an acute threatening stimulus.

Activation of 5-hydroxytryptamine-1A receptors suppresses cardiovascular responses evoked from the paraventricular nucleus.

Activation of central 5-hydroxytryptamine-1A (5-HT(1A)) receptors powerfully inhibits stress-evoked cardiovascular responses mediated by the dorsomedial hypothalamus (DMH), as well as responses evoked by direct activation of neurons within the DMH. The hypothalamic paraventricular nucleus (PVN) also has a crucial role in cardiovascular regulation and is believed to regulate heart rate and renal sympathetic activity via pathways that are independent of the DMH. In this study, we determined whether cardiovascular responses evoked from the PVN are also modulated by activation of central 5-HT(1A) receptors. In anesthetized rats, the increases in heart rate and renal sympathetic nerve activity evoked by bicuculline injection into the PVN were greatly reduced (by 54% and 61%, respectively) by intravenous administration of (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), an agonist of 5-HT(1A) receptors, but were then completely restored by subsequent administration of WAY-100635, a selective antagonist of 5-HT(1A) receptors. Microinjection of 8-OH-DPAT directly into the PVN did not significantly affect the responses to bicuculline injection into the PVN, nor did systemic administration of WAY-100635 alone. In control experiments, a large renal sympathoexcitatory response was evoked from both the PVN and DMH but not from the intermediate region in between; thus the evoked responses from the PVN were not due to activation of neurons in the DMH. The results indicate that activation of central 5-HT(1A) receptors located outside the PVN powerfully inhibits the tachycardia and renal sympathoexcitation evoked by stimulation of neurons in the PVN.

Pregnancy and the endocrine regulation of the baroreceptor reflex.

The purpose of this review is to delineate the general features of endocrine regulation of the baroreceptor reflex, as well as specific contributions during pregnancy. In contrast to the programmed changes in baroreflex function that occur in situations initiated by central command (e.g., exercise or stress), the complex endocrine milieu often associated with physiological and pathophysiological states can influence the central baroreflex neuronal circuitry via multiple sites and mechanisms, thereby producing varied changes in baroreflex function. During pregnancy, baroreflex gain is markedly attenuated, and at least two hormonal mechanisms contribute, each at different brain sites: increased levels of the neurosteroid 3alpha-hydroxy-dihydroprogesterone (3alpha-OH-DHP), acting in the rostral ventrolateral medulla (RVLM), and reduced actions of insulin in the forebrain. 3alpha-OH-DHP appears to potentiate baroreflex-independent GABAergic inhibition of premotor neurons in the RVLM, which decreases the range of sympathetic nerve activity that can be elicited by changes in arterial pressure. In contrast, reductions in the levels or actions of insulin in the brain blunt baroreflex efferent responses to increments or decrements in arterial pressure. Although plasma levels of angiotensin II are increased in pregnancy, this is not responsible for the reduction in baroreflex gain, although it may contribute to the increased level of sympathetic nerve activity in this condition. How these different hormonal effects are integrated within the brain, as well as possible interactions with additional potential neuromodulators that influence baroreflex function during pregnancy and other physiological and pathophysiological states, remains to be clearly delineated.

Topographical specificity of regulation of respiratory and renal sympathetic activity by the midbrain dorsolateral periaqueductal gray.

The midbrain periaqueductal gray (PAG) mediates the physiological responses to a wide range of stressors. It consists of four longitudinal columns that have different anatomical connections and functional properties. Previous anatomical and behavioral studies have led to the hypothesis that the dorsolateral PAG, but not the adjacent lateral and dorsomedial subregions, is a key center that integrates the behavioral response to acute psychological threatening stimuli. In this study, we tested whether, consistent with this hypothesis, activation of neurons in the dorsolateral PAG evokes a pattern of cardiovascular and respiratory responses that is distinct from that evoked from surrounding regions. Arterial pressure, heart rate, renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) were recorded simultaneously in urethane-anesthetized rats. Microinjections of very small amounts of d,l-homocysteic acid (750 pmol in 15 nl) were made in sites throughout the dorsomedial, dorsolateral, and lateral PAG subregions. Increases in RSNA of similar magnitude accompanied by small to moderate increases in arterial pressure and heart rate were evoked from all three PAG subregions. In contrast, large increases in both PNA burst rate (respiratory rate) and overall respiratory activity were evoked only from a highly circumscribed region that corresponded closely to the dorsolateral PAG subregion at an intermediate to caudal level. Within this region, the evoked increases in RSNA and respiratory activity were highly correlated (r = 0.914, P < 0.001), suggesting the possibility that a common population of "command neurons" within the dorsolateral PAG may generate both sympathetic and respiratory responses from this region.