Hypothalamic Defence Area Research Articles

Analytical evidence of heterogeneous lead accumulation in the hypothalamic defence area and nucleus tractus solitarius

Lead is a potent toxicant associated with adverse cardiovascular effects and hypertension in children. Yet, few studies have determined if autonomic dysfunction associated with lead exposure involves brain regions which regulate autonomic responses. Central autonomic nuclei such as the nucleus tractus solitarius (NTS) and hypothalamic defence area (HDA) may be particularly sensitive to lead infiltration because they are adjacent to ventricles and areas with semi-permeable blood–brain-barriers. To understand if autonomic nuclei are sensitive to lead accumulation Wistar rats were exposed to lead from the gestational period and lead levels were quantified in brain regions that regulate arterial pressure: the NTS and the HDA. Energy dispersive X-ray fluorescence (EDXRF) was used to quantify total brain lead levels and revealed no differences between exposed and control tissues; measured values were close to the detection limit (2μg/g). Electrothermal atomic absorption spectrometry (ETAAS) was also used, which has a greater sensitivity, to quantify lead. There was ∼2.1μg/g lead in the NTS and ∼3.1μg/g lead in the HDA of exposed rats, and no lead in the control rats. There were greater lead levels in the HDA (∼50%) as compared with the NTS. Pathology studies revealed more prominent lead granules in the HDA as compared with the NTS. Increased microglia and astrocyte activation was also noted in the NTS of lead exposed rats as compared with the HDA. Regional differences in neuro-inflammatory responses likely contribute to heterogeneous lead accumulation, with enhanced clearance of lead in the NTS. Future studies will resolve the mechanisms underpinning tissue-specific lead accumulation.

Neurons of the A5 region are required for the tachycardia evoked by electrical stimulation of the hypothalamic defence area in anaesthetized rats

In order to assess the possible interactions between the pontine A5 region and the hypothalamic defence area (HDA), we have examined the pattern of double staining for c-Fos protein immunoreactivity (c-Fos-ir) and tyrosine hydroxylase, throughout the rostrocaudal extent of the A5 region in spontaneously breathing anaesthetized male Sprague-Dawley rats during electrical stimulation of the HDA. Activation of the HDA elicited a selective increase in c-Fos-ir with an ipsilateral predominance in catecholaminergic and non-catecholaminergic A5 somata (P < 0.001 in both cases). A second group of experiments was done to examine the importance of the A5 region in modulating the cardiorespiratory response evoked from the HDA. Cardiorespiratory changes were analysed in response to electrical stimulation of the HDA before and after ipsilateral microinjection of muscimol within the A5 region. Stimulation of the HDA evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (P < 0.001) due to a decrease in expiratory time (P < 0.01). The respiratory response was accompanied by a pressor response (P < 0.001) and tachycardia (P < 0.001). After muscimol microinjection within the A5 region, pressor and heart rate responses to HDA stimulation were reduced (P < 0.01 and P < 0.001, respectively). The respiratory response persisted unchanged. Finally, to confirm functional interactions between the HDA and the A5 region, extracellular recordings of putative A5 neurones were obtained during HDA stimulation. Seventy-five A5 cells were recorded, 35 of which were affected by the HDA (47%). These results indicate that neurones of the A5 region participate in the cardiovascular response evoked from the HDA. The possible mechanisms involved in these interactions are discussed.

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.

Parabrachial complex glutamate receptors modulate the cardiorespiratory response evoked from hypothalamic defense area

To characterize the possible role of glutamate in the interaction between Hypothalamic Defense Area (HDA) and Parabrachial complex (PBc) nuclei, cardiorespiratory changes were analyzed in response to electrical stimulation of the HDA (1 ms pulses, 30-50 μA given at 100 Hz for 5s) before and after the microinjection of the nonspecific glutamate receptor antagonist kynurenic acid (50 nl, 5 nmol), NMDA receptor antagonist MK-801 (50 nl, 50 nmol), non-NMDA receptor antagonist CNQX (50 nl, 50 nmol) or metabotropic glutamate receptor antagonist MCPG (50 nl, 5 nmol) within the PBc. HDA stimulation evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (p<0.001) due to a decrease in expiratory time (p<0.01). The respiratory response was accompanied by a pressor (p<0.001) and a tachycardic response (p<0.001). Kynurenic acid within the lateral parabrachial region (lPB) abolished the tachycardia (p<0.001) and decreased the magnitude of blood pressure response (p<0.001) to HDA stimulation. Similarly, the magnitude of the tachycardia and the pressor response was decreased after the microinjection of MK-801 (p<0.01 and p<0.001, respectively) and CNQX (p<0.05 in both cases) into the lPB. Kynurenic acid microinjection in this region produced an inhibition of the tachypnea (p<0.001) to HDA stimulation but the respiratory response persisted unchanged after MK-801 or CNQX microinjection into the lPB. Kynurenic acid within the medial parabrachial region (mPB) abolished the tachycardia (p<0.01) and decreased the magnitude of the pressor response (p<0.001) to HDA stimulation. MK-801 and CNQX microinjection in this region decreased the magnitude of the tachycardia (p<0.05, in both cases) and pressor response (p<0.05, in both cases). The respiratory response evoked by HDA stimulation was not changed after the microinjection of kynurenic acid, MK-801 or CNQX within the mPB. No changes were observed in the cardiorespiratory response evoked to HDA stimulation after MCPG microinjection within lPB and mPB. These results indicate that glutamate PBc receptors are involved in the cardiorespiratory response evoked from the HDA. The possible mechanisms involved in these interactions are discussed.

Interaction of medullary P2 and glutamate receptors mediates the vasodilation in the hindlimb of rat

In the nucleus tractus solitarii (NTS) of rats, blockade of extracellular ATP breakdown to adenosine reduces arterial blood pressure (AP) increases that follow stimulation of the hypothalamic defense area (HDA). The effects of ATP on NTS P2 receptors, during stimulation of the HDA, are still unclear. The aim of this study was to determine whether activation of P2 receptors in the NTS mediates cardiovascular responses to HDA stimulation. Further investigation was taken to establish if changes in hindlimb vascular conductance (HVC) elicited by electrical stimulation of the HDA, or activation of P2 receptors in the NTS, are relayed in the rostral ventrolateral medulla (RVLM); and if those responses depend on glutamate release by ATP acting on presynaptic terminals. In anesthetized and paralyzed rats, electrical stimulation of the HDA increased AP and HVC. Blockade of P2 or glutamate receptors in the NTS, with bilateral microinjections of suramin (10 mM) or kynurenate (50 mM) reduced only the evoked increase in HVC by 75 % or more. Similar results were obtained with the blockade combining both antagonists. Blockade of P2 and glutamate receptors in the RVLM also reduced the increases in HVC to stimulation of the HDA by up to 75 %. Bilateral microinjections of kynurenate in the RVLM abolished changes in AP and HVC to injections of the P2 receptor agonist α,β-methylene ATP (20 mM) into the NTS. The findings suggest that HDA-NTS-RVLM pathways in control of HVC are mediated by activation of P2 and glutamate receptors in the brainstem in alerting-defense reactions.

Endocannabinoid modulation of sympathetic and cardiovascular responses to acute stress in the periaqueductal gray of the rat.

Activation of the sympathetic nervous system is fundamental to the coordinated response to stress or danger. The midbrain periaqueductal gray (PAG) contains the neural substrate required to recruit the sympathetic nervous system and organize the physiological and behavioral responses required to respond to imposed challenges. Endocannabinoids have been shown to influence associated behavioral responses. The defense response was used in this study as a working model to examine endocannabinoid modulation of the sympathetic response to acute stress in the anesthetized rat. Microinjection of the cannabinoid 1 (CB1) receptor agonist anandamide into the defense pathway of the dorsal PAG could elicit an increase in renal sympathetic nerve activity and blood pressure, twitching of the whiskers, and movement of the limbs. The response was attenuated by prior microinjection of the CB1 receptor antagonist AM-281 at the same site. Electrical stimulation of the hypothalamic defense area could evoke similar sympathoexcitatory and pressor responses, which were significantly attenuated by microinjection of AM-281 into the dorsal PAG. These data indicate that endocannabinoids can modulate the sympathetic and cardiovascular components of the acute stress response via CB1 receptors at the level of the PAG.

Cannabinoid Receptor Modulation of the Defense Response in the Dorsal Periqueductal Gray

The defense response is the coordinated reaction to physical and psychological stress, and has been validated as an experimental model of panic or fear. The hypothalamus and the midbrain periaqueductal gray (PAG) are key sites on the defense pathway from which sympathoexcitation, hypertension, tachycardia, increased muscle blood flow, analgesia, twitching of the vibrissae and hyperlocomotion can be evoked. Cannabinoids have been shown to be involved in anxiety‐related responses in the PAG and the present studies examined a role for cannabinoids in the mediation of the autonomic components of the defense response in the PAG. In anesthetized rats, microinjection of d,l‐homocysteic acid into the dorsal PAG could elicit a brisk sympathoexcitation, a pressor response and twitching of the whiskers. The hypothalamic defense area (HDA) was stimulated electrically at a site from which an intense sympathoexcitation and hypertension was evoked. The cannabinoid receptor (CB1R) antagonist AM251 was microinjected at the dorsal PAG site and the HDA stimulation was repeated. The renal sympathoexcitation was attenuated at 1 and 3 mins and the pressor response to HDA stimulation was attenuated at 3,5 and 10 mins post AM251. These data suggest that CB1R activation plays a role in the autonomic and cardiovascular responses of the defense response at the level of the dPAG. Supported by AHA Greater Midwest 0750010Z and NSF IOS 0751613.

Role of the parabrachial complex in the cardiorespiratory response evoked from hypothalamic defense area stimulation in the anesthetized rat

To analyze the role of parabrachial complex (PBc) in the modulation of cardiorespiratory response evoked from the hypothalamic defense area (HDA), cardiorespiratory changes were analyzed in spontaneously breathing anesthetised rats in response to electrical stimulation of the HDA (1 ms pulses, 30–50 μA, 100 Hz for 5 s) before and after the microinjection of muscimol (50 nl, 0.25 nmol, 5 s) within the PBc. HDA stimulation evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (p<0.001) due to a decrease in expiratory time (p<0.01). The respiratory response was accompanied by a pressor (p<0.001) and a tachycardic (p<0.001) response.Muscimol microinjection within the lateral parabrachial region (lPB) abolished the respiratory response to HDA stimulation (p<0.01) and decreased the pressor response (p<0.05). Muscimol within the medial parabrachial region and Kölliker-Fuse (mPB-KF) decreased the magnitude of the pressor (p<0.01) and tachycardic (p<0.05) responses to HDA stimulation. The respiratory response persisted unchanged.Finally, extracellular recording of putative neurons from these regions were obtained during HDA stimulation to confirm functional interaction between HDA and parabrachial regions. 105 pontine cells were recorded during HDA stimulation, 57 from the lPB and 48 from the mPB-KF. In mPB-KF 34/48 (71%) and in lPB 38/57 (67%) cells were influenced from HDA.The results indicate that neurons from different regions of the PBc have an important function in mediating the cardiorespiratory response evoked from the HDA. The possible mechanisms involved in these interactions are discussed.

Gabaergic mechanisms of hypothalamic nuclei in the expression of conditioned fear

The amygdala, the dorsal periaqueductal gray (dPAG), and the medial hypothalamus have long been recognized to be a neural system responsible for the generation and elaboration of unconditioned fear in the brain. It is also well known that this neural substrate is under a tonic inhibitory control exerted by GABA mechanisms. However, whereas there is a growing body of evidence to suggest that the amygdala and dPAG are also able to integrate conditioned fear, it is still unclear, however, how the distinct hypothalamic nuclei participate in fear conditioning. In this work we aimed to examine the extent to which the gabaergic mechanisms of this brain region are involved in conditioned fear using the fear-potentiated startle (FPS). Muscimol, a GABA-A receptor agonist, and semicarbazide, an inhibitor of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD), were used as an enhancer and inhibitor of the GABA mechanisms, respectively. Muscimol and semicarbazide were injected into the anterior hypothalamus (AHN), the dorsomedial part of the ventromedial nucleus (VMHDM), the dorsomedial (DMH) or the dorsal premammillary (PMD) nuclei of male Wistar rats before test sessions of the fear conditioning paradigm. The injections into the DMH and PMD did not produce any significant effects on FPS. On the other hand, muscimol injections into the AHN and VMHDM caused significant reduction in FPS. These results indicate that injections of muscimol and semicarbazide into the DMH and PMD fail to change the FPS, whereas the enhancement of the GABA transmission in the AHN and VMHDM produces a reduction of the conditioned fear responses. On the other hand, the inhibition of this transmission led to an increase of this conditioned response in the AHN. Thus, whereas DMH and PMD are known to be part of the caudal-most region of the medial hypothalamic defensive system, which integrates unconditioned fear, systems mediating conditioned fear select the AHN and VMHDM nuclei that belong to the rostral-most portion of the hypothalamic defense area. Thus, distinct subsets of neurons in the hypothalamus could mediate different aspects of the defensive responses.

Purinergic transmission into the NTS mediates cardiovascular adjustments during hypothalamic electrical stimulation

This study sought to determine the role of NTS purinergic receptors in cardiovascular adjustments to hypothalamic defense area electrical stimulation (HDAS). Male Wistar rats were anesthetized and prepared for mean arterial pressure (MAP), heart rate (HR), hindquarter blood flow (HQBF) and vascular conductance (HQVC) recordings. HDAS (150 μA; 0.6 ms; 100 Hz; N=6) evoked hypertension (21±5 mmHg), tachycardia (38±7 bpm) and hindquarter vasodilation indicated by the maximum peak (161±13% of baseline) and the area under the HQVC curve (AUC: 5958±778%). After bilateral microinjections of suramin (10 mM) into the NTS, pressor and HR responses to HDAS were unchanged (35±11 mmHg; 29±6 bpm respectively), whereas hindlimb vasodilation was extensively reduced (peak:71±7%, AUC: 782±180%). In another group (N=5) bilateral microinjections of PPADS (5mM) into the same NTS sites markedly reduced hypertension (16±4 mmHg vs 7±1 mmHg), tachycardia (7±2 bpm vs 2±1 bpm) and hindlimb vasodilation (max: 114±23% vs 28±9%, AUC: 3107±824% vs 145±49%) induced by HS. Basal levels of MAP, HR and HQVC remained unchanged after suramin or PPADS microinjections into the NTS. Our results indicated the participation of NTS different purinergic receptors subtypes in the hindquarter vasodilation during defense reactions.

Role of medullary glutamatergic and purinergic P2x receptors in cardiovascular adjustments during defense reactions

Previously we demonstrated that P2x receptors in the nucleus tractus solitarius (NTS) mediate muscle vasodilation induced by electrical stimulation of the hypothalamic defense area (HDA). In the present study we sought to determine the role of P2x and glutamatergic receptors located in the rostral ventrolateral medulla (RVLM) in cardiovascular responses induced by HDA stimulation.

Tempol in the Dorsomedial Hypothalamus Attenuates the Hypertensive Response to Stress in Rabbits

We have recently shown that microinjection of the superoxide dismutase mimetic tempol into the pressor region of the rostral ventrolateral medulla attenuates the cardiovascular response to mental (air-jet) stress in rabbits. In the present study, we examined the influence of tempol on the blood pressure (BP) and heart rate (HR) responses to stress in the key region of the hypothalamic defense area, the dorsomedial hypothalamus (DMH). New Zealand White rabbits were implanted with guide cannulae for microinjection into the DMH. After 2 weeks of recovery, the cardiovascular response to air-jet stress was evaluated before and after bilateral injections of equimolar doses (20 nmol) of the superoxide scavengers tempol, tiron, or 3-carbamoyl proxyl (3-CP). Microinjection of superoxide scavengers into the DMH did not alter resting BP or HR. Air-jet stress evoked a sustained increase in BP (+16 +/- 2 mm Hg) and HR (+48 +/- 5 beats/min). Tempol attenuated the pressor and tachycardic responses to air-jet stress by 39% +/- 10% and 37% +/- 8%, respectively (P < .05), without altering stress-induced tachypnea. Similarly, tiron selectively decreased the BP and HR responses to stress by 33% +/- 8% and 53% +/- 13%, respectively (P < .05). Conversely, 3-CP, which is structurally close to tempol but has a lower superoxide scavenging activity, did not alter the cardiovascular stress response, and neither did vehicle. Microinjection of tempol or tiron just outside the DMH had little effect on stress responses. This study provides first published evidence that superoxide in the DMH is important in the regulation of acute hypertensive and tachycardic responses to mental stress.

Modulation of the baroreceptor reflex by the dorsomedial hypothalamic nucleus and perifornical area

Neurons within the dorsomedial hypothalamic nucleus (DMH) and perifornical area (PeF), which lie within the classic hypothalamic defense area, subserve the cardiovascular response to psychological stress. Previous studies have shown that electrical stimulation of the hypothalamic defense area causes inhibition of the cardiac and (in some cases) sympathetic components of the baroreceptor reflex. In contrast, naturally evoked psychological stress does not appear to be associated with such inhibition. In this study, we tested the effect of specific activation of neurons within the DMH and PeF on the baroreflex control of renal sympathetic nerve activity and heart rate in urethane-anesthetized rats. Microinjection of bicuculline (a GABA(A) receptor antagonist) into the DMH caused dose-dependent increases in heart rate and renal sympathetic activity, shifted the baroreflex control of both variables to higher levels (i.e., increased the upper and lower plateaus of the baroreflex function curves, and increased the threshold, midpoint, and saturation levels of mean arterial pressure). The maximum gain of the sympathetic component of the baroreflex was also increased, while that of the cardiac component was not significantly changed. Increases in the midpoint were very similar in magnitude to the evoked increases in baseline mean arterial pressure. Microinjection of bicuculline into the PeF evoked very similar effects. The results indicate that disinhibition of neurons in the DMH/PeF region not only increases sympathetic vasomotor activity and heart rate but also resets the baroreceptor reflex such that it remains effective, without any decrease in sensitivity, over a higher operating range of arterial pressure.

Effect of stimulation of anterior hypothalamic area on urinary bladder function of the anesthetized rat.

The hypothalamus is a key area for the integration of the autonomic features of affective behavior. Hypothalamic defence area (HDA) stimulation evokes major cardiorespiratory changes as well as modifications of general autonomic activity both in the anesthetized and conscious animal. Micturition is due to an increase in pelvic parasympathetic activity and, in the cat, the anterior hypothalamus has been implicated in urinary bladder control with the demonstration of a dorsolateral vesicoconstrictor pathway and a ventromedial inhibitory pathway. In this study we have investigated the effect of electrical and chemical stimulation of the HDA on bladder pressure and contractions in rat. Female rats (n = 15) were anesthetized, paralyzed and ventilated artificially. Arterial blood pressure, heart rate, urinary bladder pressure and pelvic nerve activity were recorded. HDA was electrically (1 ms, 100 Hz, 5-10 s train at intensities up to 150 micro A) and chemically (sodium glutamate, 50 nl, 2mM) stimulated. For statistical analysis the t-test was used, data were expressed as mean +/- SEM. Values of t were taken as significant when p < 0.05.HDA stimulation at 100-150 micro A evoked changes of both mean blood pressure (mBP) and bladder pressure (BlP). However, stimulation at < 30 micro A allowed a distinction within HDA of two different regions, at the same antero-posterior and lateral level, but separated 100-150 micro m in depth, which evoked differential effects on blood pressure and urinary bladder pressure. Results show that low intensity stimulation at ventral sites evoked a significant increase of mBP (from 102 +/- 5.9 to 127 +/- 8.6 mmHg, n = 10, p < 0.0001) with little changes of BlP (from 12 +/- 2.2 to 16 +/- 2.9 cmH(2)O, n = 10, p < 0.0005), whilst at more dorsal sites significant increases of BlP were elicited (from 12 +/- 8.3 to 38 +/- 4.6 cmH(2)O,n = 10, p < 0.0001) with only a small rise of mBP (from 102 +/- 6.2 to 111 +/- 9.8 mmHg, n = 10, p < 0.005). Glutamate injections at dorsal sites evoked a rise of BlP (from 11 +/- 2.2 to 30 +/- 3.0 cmH(2)O (n = 5; p < 0.0001) with small changes in BP, whilst at ventral sites (n = 4) glutamate microinjections evoked changes in BP but not of BlP. In conclusion stimulation at different sites within HDA can elicit separate changes in BP and BlP.

Angiotensin AT1 receptor antagonist losartan and the defence reaction in the anaesthetised rat. Effect on the carotid chemoreflex.

Modulation at the level of the nucleus tractus solitarii (NTS) appears to be an effective way of controlling cardiovascular reflexes. Angiotensin II acting on angiotensin AT1 receptors at the central nervous system appears to have an important role in these modulatory processes. The hypothalamic defence area (HDA) is a potential source of descending fibres containing angiotensin II that innervate the NTS. We investigated the effect of AT1 receptor blockade in the NTS on the response to stimulation of HDA in anaesthetised rats treated with the neuromuscular blocking agent pancuronium bromide. The characteristic increase in heart rate, blood pressure and phrenic nerve activity evoked by electrical stimulation of HDA is decreased by the microinjection of the AT1 receptor antagonist losartan into the NTS and the cardiovascular response to carotid body chemical stimulation is also reduced. These results support the hypothesis that AT1 receptors in the NTS play a role in the modulation of cardiovascular reflexes, and modify the influence exerted on the processing of these reflexes by other areas of the central nervous system.

Rapid adenosine release in the nucleus tractus solitarii during defence response in rats: real-time measurement in vivo.

We have measured the release of adenosine and inosine from the dorsal surface of the brainstem and from within the nucleus tractus solitarii (NTS) during the defence response evoked by hypothalamic stimulation in the anaesthetised rat. At the surface of the brainstem, only release of inosine was detected on hypothalamic defence area stimulation. This inosine signal was greatly reduced by addition of the ecto-5'-nucleotidase inhibitor alpha,beta-methylene ADP (200 microM), suggesting that the inosine arose from adenosine that was produced in the extracellular space by the prior release of ATP. By placing a microelectrode biosensor into the NTS under stereotaxic control we have recorded release of adenosine within this nucleus. By contrast to the brainstem surface, a fast increase in adenosine, accompanied only by a much smaller change in inosine levels, was seen following stimulation of the hypothalamic defence area. The release of adenosine following hypothalamic stimulation was mainly confined to a narrow region of the NTS some 500 microm in length around the level of the obex. Interestingly the release of adenosine was depletable: when the defence reaction was evoked at short time intervals, much less adenosine was released on the second stimulus. Our novel techniques have given unprecedented real-time measurement and localisation of adenosine release in vivo and demonstrate that adenosine is released at the right time and in sufficient quantities to contribute to the cardiovascular components of the defence reaction.

The dorsomedial hypothalamus and the response to stress: Part renaissance, part revolution

Emotional stress provokes a stereotyped pattern of autonomic and endocrine changes that is highly conserved across diverse mammalian species. Nearly 50 years ago, a specific region of the hypothalamus, the hypothalamic defense area, was defined by the discovery that electrical stimulation in this area evoked changes that replicated this pattern. Attention later shifted to the hypothalamic paraventricular nucleus (PVN) owing to (1) elucidation of its role as the final common pathway mediating activation of the hypothalamic–pituitary–adrenal (HPA) axis, a defining feature of the stress response and (2) the finding that the PVN was the principal location of hypothalamic neurons that project directly to spinal autonomic regions. Consequently, a primary role for the PVN as the hypothalamic center integrating the autonomic and endocrine response to stress was inferred. However, our findings indicate that neurons in the nearby dorsomedial hypothalamus (DMH)—a region originally included in the hypothalamic defense area—and not in the PVN play a key role in the cardiovascular changes associated with emotional or exteroceptive stress. Indeed, excitation of neurons in the parvocellular PVN and consequent recruitment of the HPA axis that occurs in exteroceptive stress is also signaled from the DMH. Thus, the DMH may represent a higher order hypothalamic center responsible for integrating autonomic, endocrine and even behavioral responses to emotional stress.

Pharmacology and Physiology of Perivascular Nerves Regulating Vascular Function: Sympathetic Cholinergic Vasodilation of Skeletal Muscle Small Arteries

Recently we have studied the direct vasomotor response of the hindlimb extramuscular large arteries (internal diameter, 500-1400 microm) and intramuscular small arteries (internal diameter, 50-500 microm) of in vivo thick skeletal muscle during activation of sympathetic cholinergic nerve in anesthetized cats. The hypothalamic defense area was electrically stimulated so as to induce a profound increase in femoral blood flow mediated by sympathetic cholinergic fibers. To visualize the vascular arrangement from the extramuscular large feeding arteries to small arteries in the triceps surae muscle, we developed a new X-ray TV system. The internal diameter, flow velocity, and volume flow of arterial blood vessels were directly measured before and during stimulation of the hypothalamic defense area. The major new finding is that the hypothalamic stimulation causes an intense increase in the internal diameter of small arteries in skeletal muscle, which is abolished either by cholinergic blockade or by the section of the sciatic nerve, but not by combined alpha- and beta-adrenergic blockade. In contrast, the internal diameter of the extramuscular larger arteries does not change during the hypothalamic stimulation, but their flow velocity and volume flow increase. These findings indicate that sympathetic cholinergic vasodilation occurs at intramuscular small arteries with internal diameter of 50-500 microm, which in turn increases flow velocity and volume flow of upstream blood vessels.

A role for adenosine in modulating cardio-respiratory responses: a mini-review

Evidence is provided that purine nucleotides play a major role in modulating cardio-respiratory control through actions at specific sites in the central nervous system (CNS). The accumulation of adenosine in the extracellular space of the nucleus tractus solitarius (NTS) on hypothalamic defence area stimulation is described, and is shown to result from the extracellular breakdown of neurally released adenosine triphosphate (ATP). The actions of adenosine in modulating synaptic actions in the NTS are discussed in relation to the potential presynaptic action of adenosine in modulating transmitter release. Actions of adenosine and ATP at other sites in the medulla concerned with cardio-respiratory control are discussed. The inter-relationships between ATP and adenosine are mentioned.

Central Nervous System Control of Autonomic Function

edited by David Jordan, Harwood Academic Press, 1997. £69.00 (xiv + 304 pages) ISBN 3 7186 5141 6A series of 14 books that summarize current research issues concerning the autonomic nervous system is in the process of being published by Harwood Academic Press. The purpose of this series is to redirect thinking about autonomic control mechanisms, and this newest volume, which is edited by David Jordan, focuses on CNS control mechanisms. It contains nine chapters that deal with a range of topics, for example: the physiology of sympathetic and vagal preganglionic neurons; intrinsic spinal circuits affecting sympathetic function; neural regulation of urinary and sexual functions; effects of exercise on regional sympathetic outflow; airway regulation; electrodermal response; and the role of the cerebellum in cardiovascular and respiratory functions.This book will be most useful to more advanced researchers rather than graduate and medical students because it assumes the reader has some background knowledge regarding central autonomic regulation. Unfortunately, very few of the chapters give overviews or simplified drawings. Still, many of the chapters provide first-rate research reviews, such as the discussion regarding sympathetic preganglionic neurons (Gilbey), intrinsic, spinal sympathetic circuits (Weaver and Polosa), neural regulation of the airways (Jordan), and the politically correct chapter by McKenna and Marson describing brainstem and spinal circuits involved in sex for the male and female. Although coverage in the other chapters is generally solid, there appears to have been a long delay before going to press because the literature citations rarely include papers from, or more recent than, 1995; this limits its usefulness.Many of the chapters devote large amounts of space to the description of earlier studies that dealt with functional brain maps obtained by electrical stimulation. Because this method does not provide reliable scientific information about neural circuits, most researchers now have abandoned its use, and thus, it was surprising the editor did not curtail these discussions. Indeed, because a strong editorial hand was not exercised, the book contains some misinformation. For example, in several places in the book, the term `hypothalamic defense area' is used as if this a scientific fact; this is untenable in view of the landmark experiment by Bandler[1xBandler, R. Neurosci. Lett. 1982; 30: 183–188Crossref | PubMed | Scopus (121)See all References][1]that demonstrated that the defense response is co-ordinated by the periaqueductal gray matter, not the hypothalamus[2xBandler, R and Shipley, M. Trends Neurosci. 1994; 17: 379–389Abstract | Full Text PDF | PubMed | Scopus (710)See all References][2].Several major subjects and issues regarding autonomic research have been omitted. For example, the autonomic changes that occur during emotional responses, such as fear, were not covered. An even more important issue not discussed in this monograph concerns the use of anesthesia. Sufficient data have now been published that suggest that this might be a confounding factor that causes results to be obtained that are the opposite of those obtained in the awake state[3xKannan, H et al. Am. J. Physiol. 1989; 256: R1325–R1330PubMedSee all References][3]. Thus, a discussion of the complications caused by anesthetics would have added a lot to this book.In conclusion, this book will be a useful reference for certain specialized topics related to autonomic control, but its overall coverage is limited, often providing a litany of what was done, rather than actually serving as agent provocateur.