Microinjection of GABA antagonists into the posterior hypothalamus elicits locomotor activity and a cardiorespiratory activation

It is well known that electrical stimulation of an area (subthalamic locomotor region, STLR) of the posterior hypothalamus evokes locomotion as well as increases in cardiorespiratory activity. Uncertainty exists over whether these responses are due to stimulation of STLR neurons or to activation of fibers of passage originating outside this area. The purpose of the present study was to determine if stimulation of STLR neurons alone would elicit the cardiorespiratory and locomotor responses. Neurons were stimulated by microinjections of gamma-aminobutyric acid (GABA) antagonists (picrotoxin and bicuculline) into the posterior hypothalamus of anesthetized cats. Both picrotoxin and bicuculline produced increases in arterial pressure, heart rate and minute ventilation which were accompanied by locomotor movements of the limbs. Increases in arterial pressure, heart rate and phrenic nerve activity were also caused by picrotoxin microinjections in paralyzed, ventilated cats. Microinjections of GABA or a GABA agonist (muscimol) reversed all of these responses. In contrast, microinjection of GABA or muscimol into the STLR without a prior antagonist injection had only small, transient effects upon cardiorespiratory activity. However, microinjection of muscimol prevented the responses to a subsequent injection of bicuculline. These results indicate that: (1) stimulation of cell bodies alone in the subthalamic locomotor region of the hypothalamus produces all the cardiorespiratory and locomotor responses evoked by electrical stimulation; (2) the responses evoked by picrotoxin and bicuculline are due to an interaction with GABA receptors and (3) a GABAergic mechanism exerts a tonic depressive influence over the cardiorespiratory and locomotor systems by an action in the posterior hypothalamus.     

Effects of subthalamic nucleus stimulation and levodopa on the autonomic nervous system in Parkinson's disease

Dysfunctions of the autonomic nervous system (ANS) are common in Parkinson's disease (PD). Regarding motor disability, deep brain stimulation of the subthalamic nucleus (STN) is an effective treatment option in long lasting PD. The aims of this study were to examine whether STN stimulation has an influence on functions of the ANS and to compare these effects to those induced by levodopa. Blood pressure (BP) and heart rate (HR) during rest and orthostatic conditions, HR variability (HRV) and breathing-induced cutaneous sympathetic vasoconstriction (CVC) were tested in 14 PD patients treated with STN stimulation during "ON" and "OFF" condition of the stimulator. The effects of a single dose of levodopa on ANS were tested in 15 PD patients without DBS. STN stimulation had no influence on cardiovascular ANS functions, whereas CVC was significantly increased. In contrast, levodopa significantly lowered BP and HR at rest and enhanced orthostatic hypotension. Further, HRV, skin perfusion and temperature increased after administration of levodopa. Our results suggest that in contrast to levodopa, STN stimulation has only minor effects on autonomic functions. Since less pharmacotherapy is needed after STN stimulation, reduced levodopa intake results in relative improvement of autonomic function in deep brain stimulated PD patients.     

A5 region modulation of the cardiorespiratory responses evoked from parabrachial cell bodies in the anaesthetised rat

We have examined the importance of the A5 region modulating cardiorespiratory responses evoked from the parabrachial complex (PB) in spontaneously breathing rats. Cardiorespiratory changes were analyzed in response to electrical stimulation and glutamate microinjections into the PB (10-20 nl, 1-2 nmol) before and after ipsilateral microinjection of muscimol (50 nl, 0.25 nmol) or lidocaine (50 nl, 0.5 nmol) within the A5 region. Stimulation of medial parabrachial and K?lliker-Fuse nuclei (mPB-KF) evoked a decrease in respiratory rate (P<0.001) with a rise in blood pressure (P<0.001) and heart rate (P<0.05). After muscimol or lidocaine microinjections within the A5 region, the pressor and heart rate responses to mPB-KF stimulation were reduced (P<0.05, both cases). Muscimol within the A5 region altered the respiratory response to glutamate stimulation of mPB-KF, evoking an increase in respiratory rate (P<0.05). Lidocaine abolished the respiratory response to mPB-KF stimulation. Stimulation of the lateral parabrachial nuclei (lPB) caused an increase in respiratory rate (P<0.001) with a rise in blood pressure (P<0.001) and heart rate (P<0.05). Muscimol or lidocaine microinjections within A5 region decreased heart rate (P<0.05) and pressor responses (P<0.05) evoked from lPB. The increase of respiratory rate persisted unchanged. To confirm functional interactions between A5 and PB, extracellular recordings of putative A5 neurones were obtained during PB stimulation. Eighty-three A5 cells were recorded, 35 were activated from the mPB-KF (42%). The results indicate that neurones of the A5 region participate in the cardiorespiratory response evoked from the different regions of the PB complex. The possible mechanisms involved in these interactions are discussed.     

An investigation into the mechanism of cardiovascular responses elicited by electrical stimulation of locus coeruleus and subcoeruleus in the cat

Electrical stimulation of locus coeruleus (LC) and subcoeruleus (SC) elicited an increase in heart rate (HR) and blood pressure (BP). Adrenergic neurone blockade in the posterior hypothalamus with guanethidine and also bilateral adrenalectomy completely blocked the LC stimulation induced cardiovascular responses. The cardiovascular responses elicited by electrical stimulation of SC were, however, unaffected by the former and only partially inhibited by the latter. It is suggested that the LC stimulation-evoked rise in HR and BP is mediated by catecholamine release from the adrenal medulla due to an activation of the hypothalamic-adrenal axis. The cardiovascular responses elicited by stimulation of SC are mainly due to activation of the sympathetic preganglionic neurones and are further augmented by the adrenal catecholamine release.     

Basal ganglia neural responses during behaviorally effective deep brain stimulation of the subthalamic nucleus in rats performing a treadmill locomotion test

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease (PD). In spite of proven therapeutic success, the mechanism underlying the benefits of DBS has not been resolved. A multiple-channel single-unit recording technique was used in the present study to investigate basal ganglia (BG) neural responses during behaviorally effective DBS of the STN in a rat model of PD. Rats underwent unilateral dopamine (DA) depletion by injection of 6-hydroxyDA (6-OHDA) into one side of the medial forebrain bundle and subsequently developed a partial akinesia, which was assessed during the treadmill locomotion task. High frequency stimulation (HFS) of the STN restored normal treadmill locomotion behavior. Simultaneous recording of single unit activity in the striatum (STR), globus pallidus (GP), substantia nigra pars reticulata (SNr), and STN revealed a variety of neural responses during behaviorally effective HFS of the STN. Predominant inhibitory responses appeared in the STN stimulation site. Nearly equal numbers of excitatory and inhibitory responses were found in the GP and SNr, whereas more rebound excitatory responses were found in the STR. Mean firing rate did not change significantly in the STR, GP, and SNr, but significantly decreased in both sides of STN during DBS. A decrease in firing rate in the contralateral side of STN provides neural substrate for the clinical observation that unilateral DBS produces bilateral benefits in patients with PD. In addition to the firing rate changes, a decrease in burst firing was observed in the GP and STN. The present study indicates that DBS induces complex modulations of the BG circuit and further suggests that BG network reorganization, rather than a simple excitation or inhibition, may underlie the therapeutic effects of DBS in patients with PD.     

Deep brain stimulation of the subthalamic nucleus improves cognitive flexibility but impairs response inhibition in Parkinson disease

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN) improves motor symptoms of Parkinson disease. Although several studies have assessed cognitive functions before surgery and after long-term STN stimulation, only a few have assessed patients while stimulation is on and off to more specifically address the short-term cognitive effects of STN deep brain stimulation. OBJECTIVE: To examine the short-term effects of STN stimulation on several tests sensitive to executive function and the long-term effects of STN stimulation on a global cognitive scale. DESIGN: Twenty-three patients with Parkinson disease were tested 6 to 12 months after surgery with STN stimulation switched on and off in a random order while taking their regular medication. The Unified Parkinson's Disease Rating Scale motor score was also rated in the on and off stimulation condition. The neuropsychological battery included digit span, verbal fluency, Stroop color test, and random number generation in a single- and dual-task condition. RESULTS: Short-term stimulation improved the results on the Random Number Generation Task, requiring suppression of habitual responses, but induced more errors in the interference task of the Stroop color test. Digit span, verbal fluency, and dual-task performance results did not change. There was a significant correlation (r = 0.47, P =.02) between improved performance on the Random Number Generation Task and impaired response inhibition in the Stroop interference condition. A preoperative to postoperative comparison showed no changes in global cognitive function with long-term STN deep brain stimulation. CONCLUSIONS: Short-term STN stimulation improves cognitive flexibility (giving up habitual responses) but impairs response inhibition. Long-term STN stimulation does not change global cognitive function.     

Role of the subthalamic nucleus in the regulation of nigral dopamine neuron activity.

The influence of subthalamic nucleus (STN) afferents on dopaminergic (DA) neurons of the rat substantia nigra (SN) was investigated. Hemisections of the brain placed between the STN and the SN or located anterior to the STN caused an increase in the firing rate of DA cells without producing significant changes in their firing pattern. In contrast, electrolytic and ibotenic acid lesions of the STN resulted in 93% and 49% reductions, respectively, in the level of burst firing without affecting the firing rate of DA cells recorded in the lateral SN. Furthermore, procedures which interrupted the STN input to the SN produced rapid pacemaker-like firing in 18% of the lateral SN DA neurons recorded. Activation of the STN using single pulses of electrical stimulation caused: 1) a 20-50 msec inhibition of DA cell firing followed by an excitation, which in 35% of DA cells was accompanied by spikes occurring in a burst-like pattern, and 2) a short-latency inhibition lasting 5-25 msec in 75% of non-DA SN zona reticulata (ZR) neurons. On the other hand, stimulation of the STN for 1 minute at 20 Hz resulted in an initial decrease in DA cell burst firing followed by elevated firing rates and increased burst firing by 30-60 minutes after the stimulation. Pharmacological activation of the STN by infusion of bicuculline caused a rapid inhibition of DA cells followed by a two-fold increase in burst firing 6-14 minutes later, whereas SN ZR cells responded with an elevation in firing rate which dissipated in 6-14 minutes. Muscimol-induced STN inhibition produced complimentary biphasic changes in SN neuron firing: 1) an initial increase followed by a decrease in burst firing and firing rate of DA neurons and 2) a rapid inhibition followed by an excitation of ZR cells over a similar time course. Thus, the STN appears to exert a dual action on SN DA cells: 1) initial inhibition possibly mediated through STN excitation of the inhibitory SN ZR projections to DA cells, and 2) a facilitation of burst firing which may be a direct effect of excitatory STN afferents.     

Subthalamic nucleus lesions alter basal and dopamine agonist stimulated electrophysiological output from the rat basal ganglia

The subthalamic nucleus (STN) is an important link in the "indirect" striatal efferent pathway. To assess its role on basal ganglia output via the substantia nigra pars reticulata (SNr), we monitored the single unit activities of SNr neurons in chloral hydrate-anesthetized rats 5-8 days after bilateral kainic acid lesions (0.75 microg/0.3 microl/side) of the STN. Consistent with loss of an excitatory input, the average basal firing rate of SNr neurons was significantly reduced in STN-lesioned animals. Moreover, the lesions modified the responses of SNr neurons to individual and concurrent stimulation of striatal D1 and D2 receptors. Bilateral striatal infusions of the D1/D2 agonist apomorphine (10 microg/microl/side) into the ventral-lateral striatum (VLS) were previously shown to cause significant increases in SNr cell firing (to 133% of baseline) in normal rats. However, in STN-lesioned rats, identical infusions caused no overall change in SNr activity (mean, 103% of basal rates). Conversely, selective stimulation of striatal D2 receptors by bilateral co-infusion of the D2 agonist quinpirole and the D1 antagonist SCH 23390 that previously caused little change in SNr firing in normal rats significantly inhibited their firing in STN-lesioned rats. Finally, the modest excitatory responses of SNr neurons to selective stimulation of striatal D1 receptors by co-infusions of SKF 82958 with the D2 antagonist YM09151-2 were not altered by lesions of the STN. These results implicate the STN as a mediator of excitatory response of SNr neurons to D2, and mixed D1/D2, dopamine receptor agonists in normal rats, and challenge conventional views on the role of the STN and the "indirect" pathway in regulating dopamine-stimulated output from the SNr.     

Cardiovascular responses to electrical stimulation of the ventrolateral medulla of the spontaneously hypertensive rat

Cardiovascular responses to electrical microstimulation of the ventrolateral medulla were investigated in both Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) under pentobarbital anesthesia. The threshold intensity required to elicit a change in blood pressure (BP) and the cardiovascular responses in these two groups of rats upon electrical stimulation were compared. It was found that the region with the lowest threshold intensities was located in the rostral ventrolateral medulla (RVL) and the threshold intensities were much lower in SHR than in WKY. Electrical stimulation of this brain region also resulted in a greater increase in BP during stimulation in SHR, compared to control. In SHR, upon termination of stimulation, the BP dropped to a level above the pre-stimulation level and this was followed by a prolonged, sustained elevation in BP before returning to the control level, whereas in WKY, the BP showed an initial drop to below the pre-stimulation level and then returned to the control level. These results suggest an enhanced responsiveness to electrical stimulation in SHR. Although the heart rate (HR) increased to a similar extent during electrical stimulation in both groups of rats, upon termination of stimulation WKY exhibited bradycardia followed by tachycardia before the HR returned to the pre-stimulation level, whereas SHR exhibited tachycardia which was maintained for a substantial period of time before returning to the pre-stimulation level. The results suggest a lower baroreceptor sensitivity in SHR. The change in HR/change in BP was smaller in SHR than in WKY, suggesting that the increase in HR may not contribute to the increase in BP during stimulation as much in SHR as in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes induced by levodopa and subthalamic nucleus stimulation on parkinsonian speech.

Levodopa (L-dopa) and subthalamic nucleus (STN) stimulation treatments have been associated with both improvement and exacerbation of dysarthria in Parkinson's disease (PD). We report four cases illustrating variant responses of dysarthria to dopaminergic and STN stimulation therapies. Patients' motor disability and dysarthria were perceptually rated by the Unified Parkinson's Disease Rating Scale (UPDRS) in four conditions according to medication and STN stimulation. Dedicated software packages allowed acquisition and analysis of acoustic recordings. Case 1, who had a severe off period aphonia, experienced improvement of speech induced by both levodopa and STN stimulation. In Case 2, both treatments worsened speech due to the appearance of dyskinesias. Case 3 had a dysarthria exacerbation induced by STN stimulation with parameters above optimal levels, interpreted as current diffusion from the STN to corticobulbar fibers. In Case 4, dysarthria exacerbation occurred with stimulation at an electrode contact located caudally to the target, also arguing for current diffusion as a potential mechanism of speech worsening. The presented cases demonstrated variant effects in relation to L-dopa and STN stimulation on speech. It seems that motor speech subcomponents can be improved like other limb motor aspect, but that complex coordination of all speech anatomical substrates is not responsive to STN stimulation. These hypotheses may be helpful for better understanding and management of STN stimulation effects on motor speech and skeleton-motor subsystems.     

Pathological crying induced by deep brain stimulation

Pathological crying (PLC)—an affective gesture without any or an adequate emotion—occurs with various diseases. A recent theory suggests that PLC is caused by a disruption of higher order cortical association areas from the cerebellum which computes profiles of psychomotor responses. We report a patient with Parkinson's disease who developed PLC during stimulation of the subthalamic nucleus (STN) predominantly of the right hemisphere. Positron emission tomography imaging showed thalamo‐ponto‐cerebellar activation during such stimulation. These findings indicate that the STN and possibly also ponto‐cerebellar pathways are involved in psychomotor control and in the modulation of PLC. © 2007 Movement Disorder Society     

Cryogenic blockade of the central nucleus of the amygdala attenuates aversively conditioned blood pressure and respiratory responses

The central nucleus of the amugdala (ACE) was reversibly blocked during extinction of an aversively conditioned cardiorespiratory response in unanesthetized, freely moving cats. Cryoprobes were positioned bilaterally in the ACE of 4 cats and in the nucleus entope-duncularis of 1 cat. Blood pressure typically showed biphasic changes in response to the conditioned stimulus (CS) during non-cooling trials. Blood pressure initially dropped and then rose. Heart rate consistently dropped, and respiratory rate increased in response to the CS. ACE cooling did not alter the pre-CS baseline blood pressure, heart rate or respiratory timing, but changed the cardiorespiratory response to the CS. During ACE cooling, blood pressure and respiratory responses were greatly attenuated or abolished. No significant effect on the heart rate response was observed during ACE cooling. Cooling of a nearby structure, the nucleus entopeduncularis, did not affect blood pressure, heart rate or respiratory responses to the CS. These results support the hypothesis that the ACE plays a role in both cardiovascular and respiratory regulation during conditioned aversive responses. The study also suggests that, in cats, the predominant influence of the ACE on cardiovascular control is on blood pressure rather than on heart rate regulation.     

Cardiorespiratory responses following electrical stimulation of caudal sites in the rat medulla

A limited occipital craniotomy was conducted on urethane-anesthetized rats to expose the caudal medulla in the region of the obex. Discrete bipolar electrical stimulation was administered at sites in the dorsal medulla of spontaneously breathing rats in the vicinity of the caudal nucleus tractus solitarius (NTS) and adjacent reticular formation. Cardiorespiratory responses were recorded during microstimulation at three separate stimulating frequencies to examine the functional interaction of cardiovascular and respiratory-related neuronal elements in the NTS. Microstimulation was conducted at sites in the dorsal and medial regions of the NTS beginning at the level of the area postrema and extending posteriorly through the rostrocaudal course of the NTS; microstimulation was also conducted at midline sites in the commissural region of the NTS and the ventral and ventrolateral regions of the caudal NTS. Microstimulation of loci in the reticular formation adjacent to these NTS sites did not elicit any cardiorespiratory responses whereas stimulation of individual NTS regions elicited specific patterns of cardiorespiratory responses. Specifically, microstimulation of the dorsal and medial NTS at the level of the area postrema elicited pressor responses associated with apneic/hypopneic responses whereas stimulation of midline sites in the commissural region, dorsomedial sites caudal to the area postrema and the ventral and ventrolateral areas of the caudal regions of the NTS elicited depressor responses associated with bradycardic and apneic/hypopneic responses. The most profound respiratory effects (i.e., apnea) and heart rate responses (i.e., bradycardia) were seen following stimulation of the ventral and ventrolateral regions of the caudal NTS. These findings support the notion that the caudal NTS is a major site for coordinating cardiorespiratory afferent information in the rat and it is also apparent from this study that specific regions of the caudal NTS demonstrate a functional coexistence of cardiovascular and respiratory-related neurons. Finally, the results from this study showing the regional specificity and frequency-dependent characteristics of cardiorespiratory response patterns elicited by microstimulation suggest that the local microcircuitry and intrinsic neuronal networks in the more caudal regions of the rat NTS are more complex and heterogeneous than hitherto revealed.     

An intraspinal sympathetic preganglionic pathway: Physiologic evidence in the cat

Electrical stimulation of the zona intermedia of the lower thoracic/upper lumbar cat spinal cord resulted in increases of heart rate (HR), blood pressure (BP) and cardiac contractility (dp/dt). Sites of maximal cardiovascular response (SMCR) were localized histologically to the intermediolateral nucleus (ILN). The inotropic and chronotropic responses were abolished by spinal cord transection or hemisection two to three segments rostral to the site of stimulation. Discrete electrolytic lesions in the white matter adjacent to the ILN were also shown to markedly decrease or abolish the chronotropic and inotropic responses elicited by stimulation of a more caudal SMCR. Longitudinal spinal section resulted in decreased cardiovascular responses from an SMCR; these changes were larger on the left side and greatest for BP as compared to HR and dp/dt. These findings indicate the existence of an ascending intraspinal cardiovascular pathway located in the deep white matter adjacent to the ILN. They further suggest that this is the intraspinal sympathetic preganglionic pathway recently described anatomically.     

Network effects of subthalamic deep brain stimulation drive a unique mixture of responses in basal ganglia output

Deep brain stimulation (DBS) is a remarkably successful treatment for the motor symptoms of Parkinson's disease. High-frequency stimulation of the subthalamic nucleus (STN) within the basal ganglia is a main clinical target, but the physiological mechanisms of therapeutic STN DBS at the cellular and network level are unclear. We set out to begin to address the hypothesis that a mixture of responses in the basal ganglia output nuclei, combining regularized firing and inhibition, is a key contributor to the effectiveness of STN DBS. We used our computational model of the complete basal ganglia circuit to show how such a mixture of responses in basal ganglia output naturally arises from the network effects of STN DBS. We replicated the diversification of responses recorded in a primate STN DBS study to show that the model's predicted mixture of responses is consistent with therapeutic STN DBS. We then showed how this 'mixture of response' perspective suggests new ideas for DBS mechanisms: first, that the therapeutic frequency of STN DBS is above 100 Hz because the diversification of responses exhibits a step change above this frequency; and second, that optogenetic models of direct STN stimulation during DBS have proven therapeutically ineffective because they do not replicate the mixture of basal ganglia output responses evoked by electrical DBS.     

Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease

Microelectrode recording methods for stereotactic localization of the subthalamic nucleus (STN) and surrounding structures are described. These methods accurately define targets for chronic deep brain stimulation in the treatment of Parkinson's disease. Mean firing rates and a burst index were determined for all recorded neurons, and responses to active and passive limb and orofacial movements were tested. STN neurons had a mean firing rate of 37 ± 17 Hz (n = 248) and an irregular firing pattern (median burst index, 3.3). Movement-related activity and tremor cells were identified in the STN. Ventral to the STN, substantia nigra pars reticulata neurons had a mean rate of 71 ± 23 Hz (n = 56) and a more regular firing pattern (median burst index, 1.7). Short trains (1–2 seconds) of electrical microstimulation of STN could produce tremor arrest but were and found to be useful for localization. Compared with data from normal monkeys our findings suggest that STN neuronal activity is elevated in Parkinson's disease.     

Cardiovascular responses to gustatory and mechanical stimulation of the nasopharynx in rats

The effects of natural (mechanical and gustatory) stimulation of the nasopharynx or electrical stimulation of the pharyngeal branch of the glossopharyngeal (PH-IXth) nerve on the changes in heart rate (HR) and arterial blood pressure (BP) were investigated in paralyzed and anesthetized rats. Afferent responses in the PH-IXth nerve were also investigated. Electrical stimulation of the PH-IXth nerve elicited a tachycardia and an increase in BP. Among the gustatory (1.0 M NaCl, 0.03 M HCl, 0.03 M QHCl, 1.0 M sucrose, H₂O, and 0.9% NaCl) and mechanical stimuli applied to the nasopharynx, 1.0 M sucrose and 0.9% NaCl were ineffective in changing HR and BP; the rest of the stimuli were strongly effective as was the case with electrical stimulation of the PH-IXth nerve. Responses were evoked in the PH-IXth nerve by nasopharyngeal stimulation with the stimuli which were effective in producing cardiovascular responses. On the other hand, 1.0 M sucrose and 0.9% NaCl, which were ineffective stimuli for cardiovascular responses, did not produce any response in the PH-IXth nerve. There was a high correlation between the magnitude of the responses in the PH-IXth nerve and those of the cardiovascular system. These results indicate that gustatory and mechanical information carried in the PH-IXth nerve innervating the nasopharynx plays an important role in cardiovascular regulation as well as the sense of taste.     

Neuropeptide Y in the rostral ventrolateral medulla blocks somatosympathetic reflexes in anesthetized rats

The rostral ventrolateral medulla (RVLM) is a major integrative center of cardiovascular reflexes that modulate vasomotor tone. The functions of Neuropeptide Y (NPY) in the RVLM on cardiorespiratory responses remain unknown. Arterial blood pressure (AP), heart rate (HR), splanchnic sympathetic (sSNA) and phrenic nerve activities, and responsiveness to baro-, somatosympathetic, and chemoreflex stimulation were recorded before and after bilateral NPY injection (100 pmol, 200 nl/side) in the RVLM of vagotomized urethane-anesthetized rats (n=7). Responses were characterized by an initial increase in AP followed by prolonged hypotension (P<0.01). A similar biphasic effect was exerted on HR (P<0.01). NPY caused a large increase of sSNA (P<0.01), that gradually recovered towards baseline. Somatosympathetic responses evoked by tibial nerve stimulation were largely abolished following NPY microinjection (P<0.01), but sympathoexcitatory responses evoked by acute hypoxia or sympathoinhibition evoked by aortic depressor nerve stimulation were unchanged following NPY. There was no effect of NPY on phrenic nerve amplitude or frequency. We conclude that NPY exerts excitatory effects on sympathetic tone, but inhibits responses evoked by somatic inputs. We speculate that this apparent contradiction may be due to differential expression of NPY receptor subtypes on the soma of sympathetic premotor neurons in the RVLM and on the presynaptic terminals of neurons that comprise excitatory afferent pathways.     

High‐frequency stimulation of the subthalamic nucleus modulates neuronal activity in the lateral habenula nucleus

High‐frequency stimulation (HFS) of the subthalamic nucleus (STN) is often used to treat movement disability in advanced Parkinson's disease, but some patients experience debilitating psychiatric effects including depression. Interestingly, HFS of the STN modulates 5‐HT neurons in the dorsal raphe nucleus (DRN) which are linked to depression, but the neural substrate of this effect is unknown. Here, we tested the effect of STN stimulation on neuronal activity in the lateral habenula nucleus (LHb), an important source of input to DRN 5‐HT neurons and also a key controller of emotive behaviours. LHb neurons were monitored in anaesthetized rats using single‐unit extracellular recording, and localization within the LHb was confirmed by juxtacellular labelling. HFS of the STN (130 Hz) evoked rapid changes in the firing rate of the majority of LHb neurons tested (38 of 68). Some LHb neurons (19/68) were activated by HFS, while others (19/68), distinguished by a higher basal firing rate, were inhibited. LHb neurons that project to the DRN were identified using antidromic activation and collision testing (n = 17 neurons). Some of these neurons (5/17) were also excited by HFS of the STN, and others (7/17) were inhibited although this was only a statistical trend. In summary, HFS of the STN modulated the firing of LHb neurons, including those projecting to the DRN. The data identify that the STN impacts on the LHb‐DRN pathway. Moreover, this pathway may be part of the circuitry mediating the psychiatric effects of STN stimulation experienced by patients with Parkinson's disease.