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The ventral tegmental area (VTA), nucleus accumbens (NAcc), and prefrontal cortex (PFC) are essential for experiencing pleasure and initiating motivated behaviour. The VTA, NAcc, and PFC are connected through the medial forebrain bundle (MFB). In humans, two branches have been described: an infero-medial branch (imMFB) and a supero-lateral branch (slMFB). This study aimed to explore the associations between structural connectivity of the MFB, functional connectivity (FC) of the VTA, anhedonia, and depression severity in patients with depression. Fifty-six patients with unipolar depression and 22 healthy controls matched for age, sex, and handedness were recruited at the University Hospital of Psychiatry and Psychotherapy in Bern, Switzerland. Diffusion-weighted imaging and resting-state functional magnetic resonance imaging scans were acquired. Using manual tractography, the imMFB and slMFB were reconstructed bilaterally for each participant. Seed-based resting-state FC was computed from the VTA to the PFC. Hedonic tone was assessed using the Fawcett-Clark Pleasure Scale. We identified reduced tract volume and reduced number of tracts in the left slMFB. There was an increase in FC between the VTA and right medial PFC in patients with depression. Depression severity was associated with reduced tract volume and fewer tracts in the left slMFB. Reduced hedonic tone was associated with reduced tract volume. Conversely, reduced hedonic tone was associated with increased FC between the VTA and the PFC. In conclusion, our results suggest reduced structural connectivity of the slMFB in patients with depression. Increases in FC between the VTA and PFC may be associated with anhedonia or compensatory hyperactivity.

Parkinson's disease (PD) is a neurodegenerative movement disorder that is routinely treated with levodopa. Unfortunately, long-term dopamine replacement therapy using levodopa leads to levodopa-induced dyskinesias (LID), a significant and disabling side-effect. Clinical findings indicate that LID typically only occurs following the progression of PD motor symptoms from the unilateral (Hoehn and Yahr (HY) Stage I) to the bilateral stage (HY Stage II). This suggests the presence of some compensatory interhemispheric mechanisms that delay the occurrence of LID. We therefore investigated the role of interhemispheric connections of the nigrostriatal pathway on LID expression in a rat model of PD. The striatum of one hemisphere of rats was first injected with a retrograde tracer to label the ipsi- and cross-hemispheric nigrostriatal pathways. Rats were then split into groups and unilaterally lesioned in the striatum or medial forebrain bundle of the tracer-injected hemisphere to induce varying levels of hemiparkinsonism. Finally, rats were treated with levodopa and tested for the expression of LID. Distinct subsets emerged from rats that underwent the same lesioning paradigm based on LID. Strikingly, non-dyskinetic rats had significant sparing of their cross-hemispheric nigrostriatal pathway projecting from the unlesioned hemisphere. In contrast, dyskinetic rats only had a small proportion of this cross-hemispheric nigrostriatal pathway survive lesioning. Crucially, both non-dyskinetic and dyskinetic rats had nearly identical levels of ipsi-hemispheric nigrostriatal pathway survival and parkinsonian motor deficits. Our data suggest that the survival of the cross-hemispheric nigrostriatal pathway plays a crucial role in preventing the expression of LID and represents a potentially novel target to halt the progression of this devastating side-effect of a common anti-PD therapeutic.

Background Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (slMFB) emerges as a - yet experimental - treatment for major depressive disorder (MDD) and other treatment refractory psychiatric diseases. First experiences have been reported from two open label pilot trials in major depression (MDD) and long-term effectiveness for MDD (50 months) has been reported. Objective To give a detailed description of the surgical technique for DBS of the superolateral branch of the medial forebrain bundle (slMFB) in MDD. Methods Surgical experience from bilateral implantation procedures in n = 24 patients with MDD is reported. The detailed procedure of tractography-assisted targeting together with detailed electrophysiology in 144 trajectories in the target region (recording and stimulation) is described. Achieved electrode positions were evaluated based on postoperative helical CT and fused to preoperative high resolution anatomical magnetic resonance imaging (MRI; Philips Medical Systems, Best, Netherlands), including the pre-operative diffusion tensor imaging (DTI) tractographic information (StealthViz DTI, Medtronic, USA; Framelink 5.0, Medtronic, USA). Midcommissural point (MCP) coordinates of effective contact (EC) location, together with angles of entry into the target region were evaluated. To investigate incidental stimulation of surrounding nuclei (subthalamic nucleus, STN; substantia nigra, SNr; and red nucleus, RN) as a possible mechanism, a therapeutic triangle (TT) was defined, located between these structures (based on MRI criteria in T2) and evaluated with respect to EC locations. Results Bilateral slMFB DBS was performed in all patients. We identified an electrophysiological environment (defined by autonomic reaction, passive microelectrode recording, acute effects and oculomotor effects) that helps to identify the proper target site on the operation table. Postoperative MCP-evaluation of effective contacts (EC) shows a significant variability with respect to localization. Evaluation of the TT shows that responders will typically have their active contacts inside the triangle and that surrounding nuclei (STN, SNr, RN) are not directly hit by EC, indicating a predominant white matter stimulation. The individual EC position within the triangle cannot be predicted and is based on individual slMFB (tractography) geometry. There was one intracranial bleeding (FORESEE I study) during a first implantation attempt in a patient who later received full bilateral implantation. Typical oculomotor side effects are idiosyncratic for the target region and at inferior contacts. Conclusion The detailed surgical procedure of slMFB DBS implantation has not been described before. The slMFB emerges as an interesting region for the treatment of major depression (and other psychiatric diseases) with DBS. So far it has only been successfully researched in open label clinical case series and in 15 patients published. Stimulation probably achieves its effect through direct white-matter modulation of slMFB fibers. The surgical implantation comprises a standardized protocol combining tractographic imaging based on DTI, targeting and electrophysiological evaluation of the target region. To this end, slMFB DBS surgery is in technical aspects comparable to typical movement disorder surgery. In our view, slMFB DBS should only be performed under tractographic assistance., Graphical abstract Unlabelled Image, Highlights • The slMFB is an emerging target for DBS in therapy refractory Depression. • The therapeutic effect is related to modulation of white matter. • Surgery for slMFB DBS is tractography assisted surgery. • DBS of the slMFB is in many aspects similar to movement disorder surgery.

Background The supero-lateral medial forebrain bundle (slMFB) and the anterior thalamic radiation (ATR) play a core role in reward anticipation and motivational processes. In this study, the slMFB and the ATR were investigated in a group of depressed bipolar disorder (BD) and in healthy controls (HC) using tract length as a measure of fibre geometry and fractional anisotropy (FA) as a measure of white matter microstructure. We hypothesized reduced tract length and FA of the slMFB and the ATR in BD. We expect alterations to be driven by the melancholic subtype. Methods Nineteen depressed patients with BD and 19 HC matched for age and gender underwent diffusion-weighted magnetic resonance imaging (MRI) scans. Diffusion tensor imaging (DTI) based tractography was used to reconstruct bilateral slMFB and ATR. Mean tract length and FA were computed for the slMFB and the ATR. Mixed-model ANCOVAs and post-hoc ANCOVAs, controlling for age and intracranial volume, were used to compare tract length and FA of bilateral slMFB and ATR between HC and BD and between HC and subgroups with melancholic and non-melancholic symptoms. Results In BD we found a significantly shortened tract length of the right slMFB and ATR in BD compared to HC. Subgroup analyses showed that these findings were driven by the melancholic subgroup. Mean-FA did not differ between HC and BD. Limitations Sample size Conclusions Tract length of the right slMFB and the right ATR is reduced in BD. Those changes of fibre geometry are driven by the melancholic subtype.

Highlights • Stimulation closer to tracts was associated with better outcome in DBS for depression. • Lead placement was consistent across (non)responders w.r.t. anatomical landmarks. • Tractography-guided surgery needed to ensure tracts lie within activated tissue., Background Deep brain stimulation (DBS) is an innovative treatment for treatment-refractory depression. DBS is usually targeted at specific anatomical landmarks, with patients responding to DBS in approximately 50% of cases. Attention has recently shifted to white matter tracts to explain DBS response, with initial open-label trials targeting white matter tracts yielding much higher response rates (>70%). Objective/Hypothesis Our aim was to associate distance to individual white matter tracts around the stimulation target in the ventral anterior limb of the internal capsule to treatment response. Methods We performed diffusion magnetic resonance tractography of the superolateral branch of the medial forebrain bundle and the anterior thalamic radiation in fourteen patients that participated in our randomized clinical trial. We combined the tract reconstructions with the postoperative images to identify the DBS leads and estimated the distance between tracts and leads, which we subsequently associated with treatment response. Results Stimulation closer to both tracts was significantly correlated to a larger symptom decrease (r = 0.61, p = 0.02), suggesting that stimulation more proximal to the tracts was beneficial. Biophysical modelling indicated that 37.5% of tracts were even outside the volume of activated tissue. There was no difference in lead placement with respect to anatomical landmarks, which could mean that differences in treatment response were driven by individual differences in white matter anatomy. Conclusions Our results suggest that deep brain stimulation of the ventral anterior limb of the internal capsule could benefit from targeting white matter bundles. We recommend acquiring diffusion magnetic resonance data for each individual patient.

Deep brain stimulation (DBS) is a promising therapy to treat refractory major depressive disorder (MDD). Clinical trials have demonstrated the efficacy and safety of DBS when applied to different target areas, particularly the subgenual cingulate cortex, ventral capsule/ventral striatum, nucleus accumbens, and medial forebrain bundle. Despite a number of studies into this phenomenon, the mechanisms underlying the antidepressant effect of DBS remain poorly understood. The most relevant findings have come from preclinical assays, indicating that DBS activates the serotoninergic, catecholaminergic, and glutamatergic systems, promoting the expression of neurotrophic factors and facilitating synaptic plasticity. Thus, the antidepressant effect of DBS seems to be produced by multifactorial changes that induce widespread neuromodulation. Further studies will be necessary to discern the precise mechanism underlying the effects of DBS and to optimize the use of this technique to treat MDD.

Ghrelin is a peptide produced in the gut with a wide range of physiological functions. Recent studies have suggested it may have potential as a neuroprotective agent in models of Parkinson’s disease, reducing the impact of toxic challenges on the survival of nigral dopaminergic neurons. The presence of the ghrelin receptor (GHSR1a) on the dopaminergic neurons of the substantia nigra raises the possibility that a potential application for this property of ghrelin may be as an adjunctive neuroprotective agent to enhance and support the survival and integration of dopaminergic cells transplanted into the striatum. Thus far, inconsistent outcomes in clinical trials for fetal cell transplantation have been linked to low rates of cell survival which we hypothesize could be ameliorated by the presence of ghrelin. To explore this, we confirmed the expression of the GHSR1a and related enzymes on e14 ventral mesencephalon. To determine a functional effect, five groups of female Sprague–Dawley rats received a unilateral 6-OHDA lesion to the medial forebrain bundle and four received an intrastriatal graft of e14 ventral mesencephalic cells. Grafted rats received saline; acyl-ghrelin (10 µg/kg); acyl-ghrelin (50 µg/kg) or the ghrelin agonist JMV-2894 (160 µg/kg) i.p. for 8 weeks. An effect of ghrelin at low dose on hippocampal neurogenesis indicated blood–brain barrier penetrance and attainment of biologically relevant levels but neither acyl-ghrelin nor JMV-2894 improved graft survival or efficacy.

Following transplantation of foetal primary dopamine (DA)-rich tissue for neurorestaurative treatment of Parkinson’s disease (PD), only 5–10% of the functionally relevant DAergic cells survive both in experimental models and in clinical studies. The current work tested how a two-step grafting protocol could have a positive impact on graft survival. DAergic tissue is divided in two portions and grafted in two separate sessions into the same target area within a defined time interval. We hypothesized that the first graft creates a “DAergic” microenvironment or “nest” similar to the perinatal substantia nigra that stimulates and protects the second graft. 6-OHDA-lesioned rats were sequentially transplanted with wild-type (GFP −, first graft) and transgenic (GFP +, second graft) DAergic cells in time interims of 2, 5 or 9 days. Each group was further divided into two sub-groups receiving either 200 k (low cell number groups: 2dL, 5dL, 9dL) or 400 k cells (high cell number groups: 2dH, 5dH, 9dH) as first graft. During the second transplantation, all groups received the same amount of 200 k GFP + cells. Controls received either low or high cell numbers in one single session (standard protocol). Drug-induced rotations, at 2 and 6 weeks after grafting, showed significant improvement compared to the baseline lesion levels without significant differences between the groups. Rats were sacrificed 8 weeks after transplantation for post-mortem histological assessment. Both two-step groups with the time interval of 2 days (2dL and 2dH) showed a significantly higher survival of DAergic cells compared to their respective standard control group (2dL, + 137%; 2dH, + 47%). Interposing longer intervals of 5 or 9 days resulted in the loss of statistical significance, neutralising the beneficial two-step grafting effect. Furthermore, the transplants in the 2dL and 2dH groups had higher graft volume and DA-fibre-density values compared to all other two-step groups. They also showed intense growth of GFP + vessels – completely absent in control grafts – in regions where the two grafts overlap, indicating second-graft derived angiogenesis. In summary, the study shows that two-step grafting with a 2 days time interval significantly increases DAergic cell survival compared to the standard protocol. Furthermore, our results demonstrate, for the first time, a donor-derived neoangiogenesis, leading to a new understanding of graft survival and development in the field of cell-replacement therapies for neurodegenerative diseases.

In the 6-hydroxydopamine (6-OHDA) lesioned rodent the location of the lesion produces significantly different behavioural phenotypes, responses to the dopamine precursor l-3,4-dihydroxyphenylalanine (l-DOPA) and neuropathology. Lesion extent is commonly determined by a series of motor tests, but whether any of these tests have a relationship to the development and predictability of dyskinesia is unknown. We used mice with 6-OHDA lesions of the striatum, medial forebrain bundle and substantia nigra to examine the relationship between a range of tests used to determine motor function in the absence of l-DOPA: rotarod, cylinder, corridor, the balance beam, locomotor activity, psycho-stimulant and spontaneous rotational behaviour. The mice were subsequently treated with l-DOPA in progressively increasing doses and the development of l-DOPA-induced dyskinesia assessed. Most of these tests predict dopamine depletion but only rotarod, spontaneous rotations, apomorphine-induced rotations and locomotor activities were significantly correlated with the development of dyskinesia at 6 mg/kg and 25 mg/kg l-DOPA. The losses of dopaminergic neurons and serotonergic density in the ventral and dorsal striatum were dependent upon lesion type and were also correlated with l-DOPA-induced dyskinesia. The expression of FosB/ΔFosB was differentially affected in the striatum and nucleus accumbens regions in dyskinetic mice according to lesion type.

6-Hydroxydopamine (6-OHDA) lesions are being used in the mouse for basic research on Parkinson's disease and L-DOPA-induced dyskinesia. We set out to compare unilateral lesion models produced by intrastriatal or intramesencephalic injections of a fixed 6-OHDA concentration (3.2 μg/μl) in C57BL/6 mice. In the first experiment, toxin injections were performed either at two striatal coordinates (1 or 2 μl per site, termed "striatum(2 × 1 μl)" and "striatum(2 × 2 μl)" models), in the medial forebrain bundle (MFB), or in the substantia nigra pars compacta (SN) (1 μl per site). All the four lesion models produced significant forelimb use asymmetry, but spontaneous turning asymmetry only occurred in the MFB and striatum(2 × 2 μl) models. After the behavioral studies, the induction of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) by acute L-DOPA (30 mg/kg) was used as a marker of post-synaptic supersensitivity. Striatal pERK1/2 expression was sparse in the SN and striatum(2 × 1 μl) groups, but pronounced in the striatum(2 × 2 μl) and MFB-lesioned mice. In further experiments, mice with MFB and striatal(2 × 2 μl) lesions were used to compare behavioral and molecular responses to chronic L-DOPA treatment (12 days at 3 and 6 mg/kg/day). Maximally severe abnormal involuntary movements (AIMs) occurred in all MFB-lesioned mice, whereas only 35% of the mice with striatal lesions developed dyskinesia. Striatal tissue levels of dopamine were significantly lower in the dyskinetic animals (both MFB and striatum(2 × 2 μl) groups) in comparison with the non-dyskinetic ones. Noradrenaline levels were significantly reduced only in MFB lesioned animals and did not differ among the dyskinetic and non-dyskinetic cases with striatal lesions. In all groups, the L-DOPA-induced AIM scores correlated closely with the number of cells immunoreactive for tyrosine hydroxylase or FosB/∆FosB in the striatum. In conclusion, among the four lesion procedures examined here, only the MFB and striatum(2 × 2 μl) models yielded a degree of dopamine denervation sufficient to produce spontaneous postural asymmetry and molecular supersensitivity to L-DOPA. Both lesion models are suitable to reproduce L-DOPA-induced dyskinesia, although only MFB lesions yield a pronounced and widespread expression of post-synaptic supersensitivity markers in the striatum.

Recently, it was demonstrated that the priming stimulation effect (PSE) of intracranial self-stimulation (ICSS) with the runway method can be used as a model system to study the motivation that contributes to specific behaviors. It was postulated that these behaviors could be used to compare the effects of various drugs on the mechanism of motivation. In the present study, the influences of nicotine, methyllycaconitine (α7 nicotine-receptor antagonist), and dihydro-β-erythroidine (α4β2 nicotine-receptor antagonist) on motivation were examined using the runway method for ICSS. Electrodes were implanted into the medial forebrain bundle of Wistar rats. The rats ran to the goal lever to get the reward (50 – 200 μA, 0.2 ms, 60 Hz) and pretrial electric stimulation (priming stimulation) in the medial forebrain bundle was performed. The experiment measured the running time from the start box until the rat pressed the goal lever for the reward stimulation. Under these reward and priming stimulation conditions, nicotine (0.2 mg/kg) induced a significant increase in running speed. The nicotine receptor antagonist α4β2 rather than α7 showed a dose-dependent antagonistic action on the effect of nicotine on running speed. These results demonstrate that nicotine enhances the running speed towards the goal lever via α4β2 nicotinic receptors and suggest that α4β2 nicotinic receptors influence the brain mechanism of motivation. Keywords:: nicotine, methyllycaconitine, dihydro-β-erythroidine, intracranial self-stimulation, motivation

The most frequently used animal models for Parkinson's disease (PD) utilize unilateral injection of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB), which results in total denervation of the dopaminergic nigrostriatal pathway. However, neuroprotective interventions in PD require models resembling earlier stages of PD, where some dopaminergic cells and fibres remain. The aim of the present study was therefore to establish a MFB partial lesion model in mice. We tested four different 6-OHDA doses, and our results show a dose-dependent loss of nigral dopaminergic cells and striatal fibres that correlated with behavioural impairment in several behavioural tests. Specifically, doses of 0.7 μg and 1 μg of 6-OHDA induced a partial denervation of the nigrostriatal pathway, associated with a mild but quantifiable behavioural impairment. We identified the amphetamine-induced rotation, stepping, corridor and cylinder test to be sensitive enough to select partial lesion animals. Based on our data, we proposed a range of cut-off values for these different behavioural tests to select partial lesion mice. Using a statistical prediction model we identified two behavioural tests (the stepping test and amphetamine-induced rotation test) that with a high sensitivity and specificity predict the extent of nigral dopaminergic cell loss and select mice with a partial nigrostriatal lesion prior to further interventions. This model can serve as an important tool to study neuroprotective therapies for PD in mouse models, especially when the treatment targets the substantia nigra and/or the striatum.

Motivation is the process that mediates goal-directed responses to changes in the external or internal environment. Appetitive behavior, such as foraging for food or seeking a mate, tends to be adaptive, flexible, and learned through experience. In contrast, consummatory behavior, such as ingestion and copulation, tends to be reflexive or stereotyped and acquired early in development. The hypothalamus is critical for controlling consummatory behaviors, including drinking, thermoregulation, aggression, and sex. Studies of the role of the hypothalamus eventually led to the hypothesis that pathways coursing through the hypothalamus had a key role in motivation, reward, and incentive salience. Studies on brain stimulation reward revealed that sites that support high reward followed the trajectory of the medial forebrain bundle, leading to the hypothesis that its connections formed the basis for reward or reinforcement mechanisms in the brain. Subsequently, a major monoaminergic pathway in the medial forebrain bundle, the mesolimbic dopamine system, that projects from the ventral tegmental area to the nucleus accumbens was shown to have a key role in incentive motivation, conditioned reinforcement, and incentive salience. Another structure implicated in motivation is the amygdala, a key area for learning Pavlovian conditioned approach responses. Communication from amygdala-ventral striatal circuitry to cortical-dorsal striatal loops is currently hypothesized to be a key component of the acquisition of stimulus-response habits that lead to compulsive motivated behavior. Addiction, the ultimate pathology of motivated behavior, is a chronic relapsing disorder characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when access to the drug is prevented. In addiction, drug-taking behavior progresses from impulsivity to compulsivity in a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. The principal components of this system include the ventral tegmental area, basal forebrain (nucleus accumbens, olfactory tubercle, frontal cortex, and amygdala), and dopamine connection between the ventral tegmental area and basal forebrain, called the mesolimbic dopamine system and the opioid peptide system therein. The withdrawal/negative affect stage is commonly associated with subjective symptoms of dysphoria, negative affect, and anxiety mediated by “within-system” adaptations, including decreases in dopaminergic transmission in the nucleus accumbens during drug withdrawal, and “between-system” neuroadaptations that include corticotropin-releasing factor and dysregulation of other stress-mediating neurotransmitter systems. In the preoccupation/anticipation stage, elements of cortical control interface with basic motivational systems to elicit craving and relapse. Drug-induced reinstatement of drug seeking appears to be mediated by a prefrontal cortex glutamatergic projection to the nucleus accumbens with dopaminergic modulation. Another powerful source of relapse in human subjects is exposure to a stressor or a state of stress. Both conditions may involve activation of corticotropin-releasing factor, dynorphin, and noradrenergic systems in the central nucleus of the amygdala and bed nucleus of the stria terminalis. Molecular mechanisms, including transduction and transcription factors, provide key hypotheses regarding vulnerability to addiction within the neurocircuitries defined above. Finally, we consider the translational relevance of this basic research via clinical neuroscience studies of addiction using brain imaging methods.

A third of patients suffering from major depression cannot be helped by conventional treatment methods. These patients face reduced quality of life, high risk of suicide, and little hope of recovery. Deep brain stimulation (DBS) is under scientific evaluation as a new treatment option for these treatment-resistant patients. First clinical studies with small samples have been stimulated at the subgenual cingulate gyrus (Cg25/24), the anterior limb of the capsula interna (ALIC), and the nucleus accumbens (NAcc). Long-term antidepressant effects, augmentation of social functioning, and normalization of brain metabolism have been shown in about 50% of patients. Cognitive safety regarding attention, learning, and memory has been reported. Adverse events were wound infection, suicide, and hypomania, amongst others. Larger studies are under way to confirm these preliminary encouraging results. New hypothesis-guided targets (e.g., medial forebrain bundle, habenula) are about to be assessed in clinical trials. The application of DBS for other psychiatric diseases (e.g., bipolar disorder, alcohol dependency, opioid addiction, schizophrenia) is debated and single case studies are under way. Standards are needed for study registration, target selection, patient inclusion and monitoring, and publication of results to guarantee safety for the patients and scientific exchange.

Publisher Summary Serotonin-containing neuronal cell bodies are restricted to discrete clusters or groups of cells located along the mid­line of the brainstem. Their axons, however, innervate almost every area of the central nervous system. The combination of the hydroxyl group in the 5th position of the indole nucleus and a primary amine nitrogen serving as a proton acceptor at physiological pH makes 5-HT a hydrophilic substance. Therefore, it does not pass the lipophilic blood–brain barrier readily. The two main ascending serotonergic pathways from the midbrain raphe nuclei to the forebrain are the dorsal periven­tricular path and the ventral tegmental radiations. Both path­ways converge in the caudal hypothalamus where they join the medial forebrain bundle. Axons of dopaminergic (A8, A9, A10) and noradrenergic (A6) cell body groups also course anteriorly through the medial forebrain bundle. Numerous studies uti­lizing a variety of techniques have revealed that an increase in raphe cell firing enhances the release of 5-HT in terminal fields. The opposite effect is observed when the raphe cell fir­ing decreases. This means that drugs that change the firing rate of serotonergic soma modify the release of 5-HT as well.

Publisher Summary The role of 5-HT 6 receptors is known for the treatment of depression, anxiety, schizophrenia, cognitive disorders, obesity, and addiction; and there is evidence that 5-HT 6 receptors may also play a role in animal models of Parkinson's disease (PD), convulsive states, inflammation, and sleep. This chapter describes the 5-HT 6 receptor mediated effects to test potential antiparkinson's disease drugs. One of the behavioral paradigms to measure drug activity in PD is the behavior that 6-hydroxydopamine (OHDA)-treated rats display after unilateral 6-OHDA injection into medial forebrain bundle, which contains dopaminergic fibers that impinge striatum. In rat animal model, the intraperitoneal administrations of the 5-HT 6 receptor antagonist Ro 04-6790 reduces atropine- and scopolamine-induced ipsilateral rotations, but neither modulated amphetamine-induced ipsilateral or levodopa-induced contralateral rotations nor induced contralateral or ipsilateral turnings per se. Thus, the role of 5-HT 6 receptor antagonists is not well definite and understood as possible involvement in PD.

It has been recently shown that the substantia nigra pars reticulata (SNr) of 6-hydroxydopamine (6-OHDA)-lesioned rats, under urethane anaesthesia, manifests a prominent low frequency oscillation (LFO) of around 1Hz, synchronized with cortical slow wave activity (SWA). Nevertheless, it is poorly understood whether these electrophysiological alterations are correlated only with severe dopamine depletion or may also play a relevant pathogenetic role in the early stages of the dopamine denervation. Hence, here we recorded SNr single units and electrocorticogram (ECoG) in two models of dopamine denervation: (i) acute dopamine denervated rats, obtained by injection of tetrodotoxin (TTX), (ii) chronic dopamine depleted rats, 2 weeks after 6-OHDA lesioning. Both TTX and 6-OHDA were infused into the medial forebrain bundle (MFB). The acute TTX-mediated dopamine depletion caused a fast developing occurrence of a SNr/ECoG coherence, peaking between 0.48 and 1.22 Hz, parallel with a consistent decrease of firing rate (from 22.61 ± 7.04 to 15.35 ± 9.04 Hz) homolateraly to the infusion. Strikingly, this abnormal 1 Hz synchronization, TTX-mediated was qualitatively similar to the ECoG/SNr synchronization detectable in the 6-OHDA lesioned hemisphere (LH). In addition, TTX infusion in the un-lesioned hemispheres (UH) of 6-OHDA treated rats, produced ECoG/SNr synchronization qualitatively similar to that recordable in the LH. Hence, our data support the proposition that LFO, is tightly correlated to cortex, and represent a critical hallmark of a basal ganglia (BG) failure from the early stages of dopamine denervation.

Direct electrical stimulation of several brain sites can be powerfully rewarding. Stimulation of the lateral hypothalamic and adjacent regions of the medial forebrain bundle is most strongly rewarding and has the least side effects. The neurotransmitter dopamine plays a major role in brain stimulation reward, though dopamine-containing fibers are not the primary substrate activated at the electrode tip. Most addictive drugs potentiate the rewarding effects of the stimulation and have their own habit-forming effects within the same circuitry.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Several toxin-induced animals models simulate the motor deficits occurring in PD. Among them, the unilateral 6-hydroxydopamine (6-OHDA) model is frequently used in rats and has the advantage of presenting side-biased motor impairments. However, the behavioral consequences of a unilateral 6-OHDA-lesion have, so far, not been described in detail in mice. The aim of this study was to characterize mice with unilateral 6-OHDA-lesions placed in the median forebrain bundle using several motor behavioral tests in order to identify the most suitable predictor of nigral cell loss. Mice underwent various drug-induced (amphetamine- and apomorphine-induced rotation) and spontaneous motor tests (cylinder, rotarod, elevated body swing, and stride length test). The amphetamine-induced rotation test, the cylinder and the rotarod test were most sensitive and reliable in detecting loss of tyrosine hydroxylase-immunoreactive cells in the substantia nigra. This study demonstrates that substantial and stable unilateral 6-OHDA-induced lesions can be established in mice, and that these lesions can be functionally assessed using several different side-bias-based behavioral tests. This mouse model offers the opportunity to use transgenic mouse strains and study the interactions between genes of interest and toxins in relation to Parkinson's disease etiology in the future.

The topographical distribution of catecholaminergic nerve fibres and their anatomical relationship to cholinergic elements in the rat globus pallidus were studied. Peroxidase-antiperoxidase and two-colour immunoperoxidase staining procedures were used to demonstrate tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT) and choline acetyltransferase (ChAT) immunoreactivities, combined with acetylcholinesterase (AChE) pharmacohistochemistry. TH immunoreactive nerve fibres were seen to enter the globus pallidus from the medial forebrain bundle. The greatest density of such fibres was found in the ventral region of the globus pallidus, which was also characterized by the greatest density of ChAT immunoreactive neurons. TH immunoreactive nerve fibres showed varicose arborizations and sparse boutons, which were occasionally seen in close opposition to cholinergic structures. In all regions of the globus pallidus, there were also larger, smooth TH immunoreactive nerve fibres of passage to the caudate putamen. A smaller number of DBH immunoreactive nerve fibres and terminal arborizations were found in the substantia innominata, internal capsule and in the globus pallidus bordering these structures. A few PNMT immunoreactive nerve fibres in the substantia innominata and internal capsule did not enter the globus pallidus. Electron microscopy revealed TH immunoreactive synaptic profiles in the ventromedial area of the globus pallidus corresponding to the nucleus basalis magnocellularis of Meynert (nBM). These made mainly symmetrical and only a few asymmetrical synaptic contacts with dendrites containing AChE reaction product. The results indicate that cholinergic structures in the nBM are innervated by dopaminergic fibres and terminals, with only a very small input from noradrenergic fibres.

In terms of its anatomical distribution, serotonin is strategically placed to affect the cerebral vasculature as it is located on both sides of the neuronal–vascular axis. The serotonin system consists of clusters of neurons containing 5-HT that have extensive projections to virtually all areas of the brain. The ascending tracts, originating mainly from the dorsal and median raph6 nuclei, congregate initially in the medial forebrain bundle before dividing into specific pathways. The primary targets are the hypothalamus, olfactory bulb, thalamus, caudate putamen, hippocampus, and cerebral cortex. The principal features of this system are its topographical organization, its high divergence, and its very high density of cortical projections. Such a complex system cannot be expected to have a “single” function, a fact that is underlined by the existence of at least 16 subtypes of 5-HT receptors, almost all present within the central nervous system. Probably this monoaminergic system acts as a neuromodulator that can either depress or activate certain physiological functions that may include those mechanisms that link brain function to blood flow.

Publisher Summary Dopamine synapses in the striatum are much smaller than at the neuromuscular junction, and unless efficient mechanisms exist for its retention, diffusional efflux from the synapse is likely. To test this hypothesis in vivo , efflux evoked by a four-pulse, 100-Hz train applied to dopamine fibers in the medial forebrain bundle was compared with that evoked by a single pulse. The duration of a 100-Hz train is too rapid for appreciable uptake to occur. The observed release was 4 times the amplitude of a single pulse, providing strong evidence that dopamine normally exits the synapse during impulse flow. It has been concluded from experiments that dopamine normally escapes the synaptic cleft, diffuses into the extrasynaptic fluid, and then acts with remote receptors. Its extracellular diffusion is restricted to a few micrometers because of interaction with the dopamine transporter. The estimated amount of dopamine released per terminal per impulse from the single-pulse experiments was 1000 molecules, a value similar to that measured during release from a cultured neuron. The nonlinear relationship between dopamine release, stimulation current, and the external [Ca 2+ ] is exactly the relation anticipated for a quantized release probability associated with vesicles. Thus, according to the model used in the experiment, the quantized levels represent the population of terminals near the electrode shifting from 0 to 1 to 2 vesicles released per terminal as the amount of Ca 2+ entry increases.

Publisher Summary This chapter discusses the neurotransmitter pathways of the central nervous system. The histochemical methods have been combined with sophisticated tract-tracing techniques to define the projections of a neuron of known transmitter identity. There are several groups of noradrenaline neurons in the brainstem; they form two main systems—the locus ceruleus and the lateral tegmental. The lateral tegmental system comprises four groups of noradrenaline neurons, between caudal medulla and midbrain. Their axons ascend as a ventral noradrenergic pathway in the central tegmental tract, traversing the diencephalon in the medial forebrain bundle to reach the septal area. This system contributes a major innervation to most of the hypothalamus. In contrast to the locus ceruleus, distribution to the telencephalon is relatively limited and includes the olfactory cortex and amygdaloid nuclei. The main functional significance of the lateral tegmental system is its noradrenaline innervation of the hypothalamus. Noradrenaline is involved in the regulation of the secretion of gonadotrophin, adrenocorticotrophic hormone, and growth hormone.

Publisher Summary This chapter discusses the olfactory and limbic systems. The olfactory epithelium in humans occupies only about one square inch in the nasal roof. It contains neurosensory cells and bipolar neurons whose peripheral processes have ciliated receptors that are sensitive to odiferous substances dissolved or suspended in the overlying mucus. The limbic system is named so because it occupies a bordering zone or limbus between the diencephalon and telencephalon. Functionally, the limbic system is intermediate between the emotive and cognitive aspects of consciousness. The limbic system has an important role in memorization. The major limbic components are the septal area, cingulate and parahippocampal gyri, hippocampal formation, amygdaloid nucleus, mamillary bodies, and anterior thalamic nucleus. Limbic pathways include the fornix, mamillothalamic tract, cingulum, stria terminalis, medial, and lateral longitudinal striae. Output to the brainstem is via the medial forebrain bundle, stria medullaris thalami, and mamillotegmental tract.

Publisher Summary This chapter examines the behavioral effects of intracerebral dopaminergic grafts after neonatal destruction of the mesencephalic dopaminergic system. Embryonic dopaminergic neurons are implanted in rat pups following the destruction of their mesotelencephalic dopaminergic system. The presence of deficits in various behaviors is evaluated once the animals reached adulthood. The behavioral deficits chosen are mainly those for which it was known, that they are not alleviated following implantation to adult animals: deficits in hoarding behavior, in schedule-induced polydipsia, and in spatial orientation. Locomotors activation by dopaminergic drugs, which are classically influenced by the implants of dopaminergic neurons in adult hosts, is also examined in the chapter. In an experiment described in the chapter, three-day-old male rats were positioned in a stereotaxic apparatus under light ether anesthesia and the mesotelencephalic dopamine (DA) system was destroyed bilaterally by injecting 6-hydroxydopamine (6-OHDA, 8 μg/side) into the medial forebrain bundle. The main functional effect of the implanted dopaminergic neurons that could be detected in the present experiment was their influence on the drug-induced locomotor activation. The reinstatement of the amphetamine-induced activation indicates that the grafted neurons, if stimulated, could have a functional influence in the host brain.

Publisher Summary This chapter examines the differential regulation of dopamine metabolism in solid fetal substantia nigra transplants and their terminals in the host striatum. Male Sprague–Dawley rats, weightng 300 g at the start of the experiment, were used in an experiment described in the chapter. They were group housed in standard laboratory cages with unlimited access to water and standard laboratory food. Room temperature was maintained at 21°C and a 12:12 light/dark cycle was in effect. The rats received a micro-injection of 6-hydroxydopamine (6-OHDA) into the left medial forebrain bundle to destroy the ascending dopamine (DA) projections. The rats were evaluated for their turning behavior after a challenge both with apomorphine (APO) (0.5 mg/kg s.c.) and, separately, with amphetamine (AMPH) (5 mg/kg i.p.) This behavioral testing was performed before transplantation and again at least 3 months following transplantation. All the rats successfully lesioned with 6-OHDA showed strong ipsilateral and contralateral turning behavior after challenge, respectively, with AMPH and APO. The DA content in the transplant itself was higher than that of the adjacent 6-OHDA lesioned striatum, with a significant difference between the transplants of the compensated as compared to that of the noncompensated rats.

Publisher Summary This chapter focuses on the interactions of self-stimulation behavior and some humoral factors. Changes in plasma corticosterone levels, hypothalamic and mesencephalic serotonin contents, and self-stimulation (SS) behavior are investigated in rats after electrical stimulation (ES) or SS of the medial forebrain bundle (MFB) region, and following injection of cholinergic drugs into the nucleus raphe dorsalis or the lateral ventricle. The results indicate that both serotoninergic and cholinergic systems are important in the organization of SS behavior. Cholinergic drugs injected into the lateral ventricle increased the plasma corticosterone level and decreased the hypothalamic and the mesencephalic serotonin contents, and the rate of SS.