[Show abstract][Hide abstract] ABSTRACT: Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN.
Full-text · Article · Mar 2015 · Translational Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Nicotine directly regulates striatal dopamine (DA) neurotransmission via presynaptic nicotinic acetylcholine receptors (nAChRs) that are α6β2 and/or α4β2 subunit-containing, depending on region. Chronic nicotine exposure in smokers upregulates striatal nAChR density, with some reports suggesting differential impact on α6- or α4-containing nAChRs. Here, we explored whether chronic nicotine exposure modifies striatal DA transmission, whether the effects of acute nicotine on DA release probability persist and whether there are modifications to the regulation of DA release by α6-subunit-containing (*) relative to non-α6* nAChRs in nucleus accumbens (NAc) and in caudate-putamen (CPu). We detected electrically evoked DA release at carbon-fiber microelectrodes in striatal slices from mice exposed for 4-8 weeks to nicotine (200 μg/mL in saccharin-sweetened drinking water) or a control saccharin solution. Chronic nicotine exposure subtly reduced striatal DA release evoked by single electrical pulses, and in NAc enhanced the range of DA release evoked by different frequencies. Effects of acute nicotine (500 nm) on DA release probability and its sensitivity to activity were apparent. However, in NAc there was downregulation of the functional dominance of α6-nAChRs (α6α4β2β3), and an emergence in function of non-α6* nAChRs. In CPu, there was no change in the control of DA release by its α6 nAChRs (α6β2β3) relative to non-α6. These data suggest that chronic nicotine subtly modifies the regulation of DA transmission, which, in NAc, is through downregulation of function of a susceptible population of α6α4β2β3 nAChRs. This imbalance in function of α6:non-α6 nAChRs might contribute to DA dysregulation in nicotine addiction.
Full-text · Article · Jul 2013 · European Journal of Neuroscience
[Show abstract][Hide abstract] ABSTRACT: The periodicity of brain activity became obvious even after the first attempt to capture it, with Hans Berger noting in 1929 that the “electroencephalogram represents a continuous curve with continuous oscillations”. This rhythmicity of neural activity, the ‘melody’ of the brain, has since gained interest as an energy-efficient strategy for the organisation and communication both within and between brain regions. While it is now known that these oscillations actively contribute to sensory perception and cognition in the adult brain, their function during development is still largely unknown. Recent experimental data revealed the ability of immature human and rodent brain to generate various patterns of electrical activity. Their properties and underlying mechanisms may vary among different brain areas. However, these early patterns of activity seem to facilitate the refinement of cortical maps involved in sensory perception as well as mnemonic and executive processing. Here we review recent studies, which characterize the early oscillatory activity and demonstrate its impact on brain development.
[Show abstract][Hide abstract] ABSTRACT: It is well established that deep brain stimulation (DBS) of the subthalamic nucleus (STN) has beneficial effects on motor symptoms of Parkinson’s disease (PD). Unfortunately, these can be overshadowed by psychiatric side effects, including depression and suicide. The underlying mechanism is unknown, but it is generally believed that low mood is related to a dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system. Recent animal experiments have demonstrated that bilateral STN DBS with clinically relevant parameters (130 Hz, 60 μs, 100–200 μA) inhibits 5-HT neurotransmission in the brain. In anaesthetized rats bilateral STN DBS caused a significant inhibition of 5-HT neuronal activity in the dorsal raphe nucleus (DRN). Moreover, both unilateral and bilateral STN DBS inhibited 5-HT release in the forebrain of anaesthetized and freely moving rats. A direct STN projection to the DRN does not exist, making a multisynaptic pathway most likely. On the basis of increased expression of c-Fos, a marker of neuronal activity, it was found that the medial prefrontal cortex and lateral habenula potentially mediate the inhibitory effect of STN DBS on the DRN 5-HT system. Previously these two brain regions have been extensively described in inhibitory control of DRN 5-HT neurons. Behavioural evaluation showed that bilateral STN DBS also induced depressive-like behaviour in the forced swim test and increased interaction in the social interaction test. Interestingly, depressive-like behaviour could be prevented by treatment with a 5-HT reuptake inhibitor. Thus, STN DBS induced inhibition of 5-HT transmission via a multisynaptic anatomical pathway may underlie the development of psychiatric complications such as depression. STN DBS treated patients with these symptoms may benefit from drug treatment focusing on 5-HT transmission.
[Show abstract][Hide abstract] ABSTRACT: Movement disability in advanced Parkinson's disease (PD) can be treated by high frequency stimulation (HFS) of the subthalamic nucleus (STN) but some patients experience psychiatric side-effects including depression, which is strongly linked to decreases in 5-hydroxytryptamine (5-HT). The current study investigated the effect of bilateral STN HFS on extracellular 5-HT in brain regions of anesthetized and freely moving rats as measured with microdialysis. Parallel in vivo electrophysiological experiments allowed a correlation of changes in extracellular 5-HT with the firing of 5-HT neurons. Bilateral STN HFS decreased (by up to 25%) extracellular levels of 5-HT in both striatum and medial prefrontal cortex of anesthetized rats. STN HFS also decreased extracellular 5-HT in the medial prefrontal cortex of freely moving rats. This decrease in extracellular 5-HT persisted after turning off the stimulation, and was present in dopamine-denervated rats. As with changes in extracellular 5-HT, in anesthetized rats STN HFS evoked a decrease in the in vivo firing of midbrain raphe 5-HT neurons that also persisted after cessation of stimulation. These data provide neurochemical evidence for an inhibition of 5-HT neurotransmission by STN HFS, which may contribute to its psychiatric side effects and guide therapeutic options.
[Show abstract][Hide abstract] ABSTRACT: Depression is the most common neuropsychiatric co-morbidity in Parkinson's disease (PD). The underlying mechanism of depression in PD is complex and likely involves biological, psychosocial and therapeutic factors. The biological mechanism may involve changes in monoamine systems, in particular the serotonergic (5-hydroxytryptamine, 5-HT) system. It is well established that the 5-HT system is markedly affected in the Parkinsonian brain, with evidence including pathological loss of markers of 5-HT axons as well as cell bodies in the dorsal and median raphe nuclei of the midbrain. However, it remains unresolved whether alterations to the 5-HT system alone are sufficient to confer vulnerability to depression. Here we propose low 5-HT combined with altered network activity within the basal ganglia as critically involved in depression in PD. The latter hypothesis is derived from a number of recent findings that highlight the close interaction between the basal ganglia and the 5-HT system, not only in motor but also limbic functions. These findings include evidence that clinical depression is a side effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN), a treatment option in advanced PD. Further, it has recently been demonstrated that STN DBS in animal models inhibits 5-HT neurotransmission, and that this change may underpin depressive-like side effects. This review provides an overview of 5-HT alterations in PD and a discussion of how these changes might combine with altered basal ganglia network activity to increase depression vulnerability.
[Show abstract][Hide abstract] ABSTRACT: High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is an established neurosurgical therapy for movement disability in advanced Parkinson's disease (PD), but some patients experience psychiatric side-effects like depression. In a previous electrophysiological study, we observed that HFS of the STN inhibited a population of neurones in the rat dorsal raphe nucleus (DRN), with firing properties characteristic of 5-HT neurones. The present study extended these findings to a second population of neurones, and combined extracellular recording with juxtacellular-labelling to investigate the chemical identity of the neurones affected by HFS. Bilateral HFS (130 Hz, 100-200 μA, 5 min) of the STN inhibited (26.0±2.9%) the firing of 37/74 DRN neurones displaying a slow, regular firing pattern. Slower firing neurones were more strongly inhibited than those firing faster. Importantly, 10 inhibited DRN neurones were juxtacellular-labelled with neurobiotin, and all neurones contained 5-HT as shown by post-mortem 5-HT immunocytochemistry. A minority of slow firing DRN neurones (18/74) were activated by STN HFS (37.9±8.3%) which was not observed previously. Of these neurones, three were juxtacellular-labelled and one was 5-HT immunopositive. Also a small number of DRN neurones (19/74) did not respond to HFS, four of which were juxtacellular-labelled and all contained 5-HT. These data show that individual chemically-identified 5-HT-containing neurones in the DRN were modulated by STN HFS, and that the majority were inhibited but some were activated and some failed to respond. These data extend previous findings of modulation of the 5-HT system by STN HFS but suggest a destabilisation of the 5-HT system rather than simple inhibition as indicated previously. Although the mechanism is not yet known, such changes may contribute to the psychiatric side-effects of STN stimulation in some PD patients.
[Show abstract][Hide abstract] ABSTRACT: Dopamine (DA) neurotransmission in the nucleus accumbens (NAc) is critically involved in normal as well as maladaptive motivated behaviors including drug addiction. Whether the striatal neuromodulator nitric oxide (NO) influences DA release in NAc is unknown. We investigated whether exogenous NO modulates DA transmission in NAc core and how this interaction varies depending on the frequency of presynaptic activation. We detected DA with cyclic voltammetry at carbon-fiber microelectrodes in mouse NAc in slices following stimuli spanning a full range of DA neuron firing frequencies (1-100 Hz). NO donors 3-morpholinosydnonimine hydrochloride (SIN-1) or z-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA/NONOate) enhanced DA release with increasing stimulus frequency. This NO-mediated enhancement of frequency sensitivity of DA release was not prevented by inhibition of soluble guanylyl cyclase (sGC), DA transporters, or large conductance Ca(2+)-activated K(+) channels, and did not require glutamatergic or GABAergic input. However, experiments to identify whether frequency-dependent NO effects were mediated via changes in powerful acetylcholine-DA interactions revealed multiple components to NO modulation of DA release. In the presence of a nicotinic receptor antagonist (dihydro-β-erythroidine), NO donors increased DA release in a frequency-independent manner. These data suggest that NO in the NAc can modulate DA release through multiple GC-independent neuronal mechanisms whose net outcome varies depending on the activity in DA neurons and accumbal cholinergic interneurons. In the presence of accumbal acetylcholine, NO promotes the sensitivity of DA release to presynaptic activation, but with reduced acetylcholine input, NO will promote DA release in an activity-independent manner through a direct action on dopaminergic terminals.
Full-text · Article · Apr 2011 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide (NO) is a well-established striatal neuromodulator, effecting both the activity and electrical coupling of striatal projection neurons. The NO-producing interneurons within the striatum are altered in schizophrenia brain tissue, and they may be key to the pathophysiology and future treatment of schizophrenia. We investigated in vivo the effect of locally applied NO-active drugs on the firing rate of electrophysiologically and anatomically identified, medium-sized densely spiny neurons and interneurons in the ventral striatum.
Juxtacellular recording and labelling experiments were performed on ventral striatal neurons during prefrontal cortex electrical stimulation. A NO donor, precursor or scavenger were applied microiontophoretically and single unit responses were recorded; after labelling, neurons were examined morphologically to determine neuronal type.
Correlation of electrophysiological and anatomical findings revealed four drug response profiles and four types of neurons. The nitrergic modulation of ventral striatal neurons is neuronal-type specific and may be effector-mechanism dependent, and it is involved in the gating of cortically driven ventral striatal output and the temporal and spatial synchrony of the striatal networks.
[Show abstract][Hide abstract] ABSTRACT: Modulation of striatal dopamine (DA) neurotransmission plays a fundamental role in the reinforcing and ultimately addictive effects of nicotine. Nicotine, by desensitizing beta2 subunit-containing (beta2*) nicotinic acetylcholine receptors (nAChRs) on striatal DA axons, significantly enhances how DA is released by reward-related burst activity compared to nonreward-related tonic activity. This action provides a synaptic mechanism for nicotine to facilitate the DA-dependent reinforcement. The subfamily of beta2*-nAChRs responsible for these potent synaptic effects could offer a molecular target for therapeutic strategies in nicotine addiction. We explored the role of alpha6beta2*-nAChRs in the nucleus accumbens (NAc) and caudate-putamen (CPu) by observing action potential-dependent DA release from synapses in real-time using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in mouse striatal slices. The alpha6-specific antagonist alpha-conotoxin-MII suppressed DA release evoked by single and low-frequency action potentials and concurrently enhanced release by high-frequency bursts in a manner similar to the beta2*-selective antagonist dihydro-beta-erythroidine (DHbetaE) in NAc, but less so in CPu. The greater role for alpha6*-nAChRs in NAc was not due to any confounding regional difference in ACh tone since elevated ACh levels (after the acetylcholinesterase inhibitor ambenonium) had similar outcomes in NAc and CPu. Rather, there appear to be underlying differences in nAChR subtype function in NAc and CPu. In summary, we reveal that alpha6beta2*-nAChRs dominate the effects of nicotine on DA release in NAc, whereas in CPu their role is minor alongside other beta2*-nAChRs (eg alpha4*), These data offer new insights to suggest striatal alpha6*-nAChRs as a molecular target for a therapeutic strategy for nicotine addiction.