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This paper presents a novel model of tremor in Parkinson's disease (PD) based on extensive literature review as well as novel results stemming from functional stereotactic neurosurgery for the alleviation of tremor in PD. Specifically, evidence that suggests the basal ganglia induces PD tremor via excessive inhibitory output to the thalamus and altered firing patterns which in turn generate rhythmic bursting activity of thalamic cells is presented. Then, evidence that the thalamus generates PD tremor by facilitating the generation and consolidation of rhythmic bursting activity of neurons within its nuclei is also offered. Finally, evidence that the cerebellum may modulate characteristics of PD tremor by treating it as if it was a voluntary motor behavior is presented. Accordingly, the current paper proposes that PD tremor is induced by abnormal basal ganglia activity; it is generated by the thalamus, and modulated or reinforced by the cerebellum., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.) more...

DCC (deleted in colorectal cancer), a receptor for the axon guidance cue netrin-1, is highly expressed by mesencephalic dopaminergic (DA) neurons during development; however, the contribution of DCC to DA development remains largely uncharacterized. DA neurons in ventral mesencephalic nuclei also express UNC5 homologue netrin receptors from late embryogenesis to adulthood, raising the possibility that DA axons could be attracted or repelled by netrins. Examining newborn dcc null mice, we report that loss of DCC function results in profound alterations of DA circuitry, including DA progenitor cell migration defects, reduced numbers of DA cells in midbrain nuclei, an anomalous DA ventral commissure, malformed DA innervation of the ventral striatum, and reduced DA innervation of the cerebral cortex. Caspase-3 activation was detected in inappropriately localized DA cells, consistent with apoptosis contributing to reduced cell numbers. Dcc heterozygous mice express reduced levels of DCC protein. Although less severely disrupted than dcc nulls, newborn and adult dcc heterozygotes also have fewer DA neurons in ventral mesenscephalic nuclei. Despite the reduced numbers of DA neurons, newborn dcc heterozygotes and nulls exhibit similar DA innervation density as wild-type littermates in the nucleus accumbens core, and adult dcc heterozygotes exhibit increased DA innervation in medial prefrontal cortex. A trend towards increased innervation of medial prefrontal cortex was detected in newborn dcc heterozygotes, but did not reach statistical significance, suggesting that the increase in adult heterozygotes results from enhanced DA arborization during postnatal development. Consistent with the hypothesis that DCC regulates DA axonal projections, disrupting DCC function in culture inhibits netrin-1 induced DA axon extension and axon branching. Furthermore, disrupting DCC function in isolated DA neurons grown as micro-island cultures reduces the number of autaptic synapses per cell. We conclude that DCC regulates appropriate precursor cell migration, axon guidance, and terminal arborization by DA neurons., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.) more...

Netrins are a family of secreted proteins that function as axon guidance cues during neural development. High levels of netrin-1 expressed by the embryonic ganglionic eminence, the precursor of the adult striatum, direct axons that pioneer the internal capsule. Here we describe netrin-1 expression by neurons distributed throughout the striatum of the adult mouse. Differences were detected in the number and type of neurons expressing netrin-1 in different regions of the striatum. Most neurons in the ventral striatum, including projection neurons and cholinergic interneurons, express netrin-1. In contrast, netrin-1 expression is largely limited to cholinergic interneurons in the dorsal striatum, and the proportion of cholinergic interneurons that express netrin-1 decreases along rostral-caudal and ventral-dorsal axes. Regional differences in expression in the adult striatum suggest that netrin-1 not only influences the development of striatal circuitry but may also participate in the maintenance and plasticity of connections in the adult brain. more...

Major classical neurotransmitters including GABA and glutamate play novel morphogenic roles during development of the mammalian CNS. During forebrain neurogenesis, glutamate regulates neuroblast proliferation in different germinal domains using receptor subtype-specific mechanisms. For example, ionotropic N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptors mediate distinct proliferative effects in ventral or dorsal forebrain germinal domains, and regulate the correct number of neurons that populate the striatum or cerebral cortex. Recent work suggests metabotropic receptors may also mediate glutamate's proliferative effects. Group I mGluR5 receptor subtypes are highly expressed in forebrain germinal zones. Using in vitro and in vivo methods, we demonstrate mGluR5 receptor activation plays an important role in neuroblast proliferation in the ventral telencephalon, and helps determine the complement of striatum projection neurons. mGluR5 receptor-mediated effects on striatal neuronal progenitors are restricted mainly to early cycling populations in the ventricular zone, with little effect on secondary proliferative populations in the subventricular zone. In contrast to proliferative effects in the ventral telencephalon, mGluR5 receptors do not modulate proliferation of dorsal telencephalon-derived cortical neuroblasts. Heterogeneous domain-specific proliferative effects of glutamate-mediated by specific receptor subtypes provide an important developmental mechanism allowing generation of the correct complement of neuronal subtypes that populate the mammalian forebrain. more...

Beta oscillations (15-30 Hz) constitute an important electrophysiological signal recorded in the resting state over the human precentral gyrus. The brain circuitry involved in generating the beta oscillations is not well understood but appears to involve both cortical and subcortical structures. We have shown that single pulses of transcranial magnetic stimulation (TMS) applied over the primary motor cortex consistently elicit a brief beta oscillation. Reducing the local cortical excitability using low-frequency repetitive TMS does not change the amplitude of the induced beta oscillation (Van Der Werf and Paus in Exp Brain Res DOI 10.1007/s00221-006-0551-2). Here, we investigated the possible involvement of the thalamus in the cortically expressed beta response to single-pulse TMS. We included eight patients with Parkinson's disease who had undergone unilateral surgical lesioning of the ventrolateral nucleus of the thalamus. We administered 50 single pulses of TMS, at an intensity of 120% of resting motor threshold, over the left and right primary motor cortex and, at the same time, recorded the electroencephalogram (EEG) using a 60-electrode cap. We were able to perform analyses on seven EEG data sets and found that stimulation of the unoperated hemisphere (with thalamus) resulted in higher amplitudes of the single-trial induced beta oscillations than in the operated hemisphere (with thalamotomy). The beta oscillation obtained in response to pulses applied over the unoperated hemisphere was also higher than that obtained in healthy controls. We suggest that (1) the beta oscillatory response to pulses of TMS applied over the primary motor cortex is higher in Parkinson's disease patients, (2) thalamotomy serves to reduce the abnormally high TMS-induced beta oscillations, and (3) the motor thalamus facilitates the cortically generated oscillation, through cortico-subcortico-cortical feedback loops. more...

Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo. more...

The critical role of the subthalamic nucleus (STN) in the control of movement and parkinsonian symptoms is well established. Research in animals suggests that the cerebral cortex plays an important role in regulating the activity of the STN but this control is not known in humans. The most extensive cortical innervation of the STN originates from motor areas. Here, we used transcranial magnetic stimulation (TMS) during intraoperative single-unit recordings from STN, in six patients with Parkinson's disease (PD) undergoing implantation of deep brain stimulators, to determine whether TMS of the motor cortex (MC) modulates the activity of STN and to investigate in vivo the functional organization of the corticosubthalamic circuit in the human brain. Single-pulse TMS of the MC induced an excitation in 74.9% of neurons investigated. This activation was followed by a long-lasting inhibition of the STN neuronal activity that did not correlate with PD severity. Responsive neurons to TMS of the hand area of motor cortex were located mainly in the lateral and dorsal region of the subthalamus while unresponsive cells had a prevalently medial distribution. This is the first report of TMS-induced modulation of STN neuronal activity in humans. These findings open up new avenues for in vivo studies of corticosubthalamic interactions in human brain and PD. more...

Increasing evidence suggests that classical neurotransmitters play an important morphogenetic role during development of the mammalian central nervous system. Using in vitro and in vivo models, we have previously identified a role for the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors in the proliferation of striatal progenitors. Here, we compare the roles of ionotropic glutamate receptors in the proliferation of either striatal or cortical progenitors. In culture, glutamate receptor activation promoted proliferation of both striatal and cortical neuroblasts. However, cortical and striatal neuroblasts responded to distinct ionotropic receptors. Cortical cultures were sensitive to AMPA/KA receptor blockade, whereas striatal neuroblast proliferation was altered by NMDA antagonists. In vivo, BrdU uptake in the proliferative ventricular zone was reduced in embryos following acute administration of ionotropic glutamate receptor antagonists. In keeping with in vitro observations, proliferation in cortical and striatal ventricular regions was reduced, respectively, by either AMPA/KA or NMDA receptor blockade. We also determined whether forebrain-derived progenitors expanded as neurospheres in the presence of growth factors show similar ionotropic glutamatergic responses. Cells in neither dorsal nor ventral telencephalon-derived neurospheres showed altered proliferation following exposure to either class of ionotropic glutamate receptor antagonist. Together, these findings suggest that glutamate influences the proliferation of forebrain neuronal progenitors, but not more primitive populations represented in multipotential progenitors expanded in vitro. The effects on neuroblast proliferation in different forebrain domains are heterogeneous and are mediated by distinct subclasses of ionotropic glutamate receptors., (Copyright 2004 S. Karger AG, Basel.) more...

Increasing evidence suggests that classical neurotransmitters play important roles in the development of the mammalian CNS. We used in vivo and in vitro models to identify a novel role for glutamate in striatal neurogenesis mediated by NMDA receptors. In utero exposure to NMDA receptor antagonists during striatal neurogenesis caused a dramatic reduction in the total number of adult striatal neurons. In contrast, embryos exposed to NMDA receptor antagonists immediately after the main period of neurogenesis showed no significant change in neuronal number in the adult striatum. In addition, examination of embryos shortly after NMDA receptor blockade revealed reduced proliferation in the lateral ganglionic eminence (LGE). In culture, dividing neuronal progenitors derived from the embryonic LGE showed marked reduction in 5'-bromodeoxyuridine (BrdU) uptake when exposed to NMDA receptor antagonists, indicating reduced DNA synthesis. Low concentrations of NMDA significantly increased proliferation, whereas high concentrations were toxic. AMPA-KA receptor antagonists had no significant effect on striatal neuroblast proliferation either in vivo or in vitro. These results support the hypothesis that glutamate plays a novel role during early development of the ventral telencephalon, promoting proliferation of striatal neuronal progenitors by an NMDA receptor-dependent mechanism. In contrast, previous findings suggest that proliferation of cortical progenitors derived from the dorsal telencephalon is regulated by activation of AMPA-KA but not NMDA receptors. Heterogeneous responses to glutamate in different germinal zones of the telencephalon may be an important mechanism contributing to generating neuronal diversity in the forebrain. more...

Here, we show that the p53 family member, p73, is necessary for survival and long-term maintenance of CNS neurons, including postnatal cortical neurons. In p73-/- animals, cortical neuron number is normal at birth but decreases significantly by postnatal day 14 (P14)-P16 because of enhanced apoptosis. This decrease continues into adulthood, when p73-/- animals have approximately one-half as many cortical cells as their wild-type littermates. Cortical neurons express the DeltaNp73alpha protein, and overexpression of DeltaNp73 isoforms rescues cortical neurons from diverse apoptotic stimuli. Thus, DeltaNp73 isoforms are survival proteins in cortical neurons, and their deletion causes a gradual loss of cortical neurons in the weeks and months after birth. This decrease in CNS neuron number in p73-/- animals is not limited to the cortex; facial motor neuron number is decreased, and postnatal development of the olfactory bulb is greatly perturbed. These findings, together with our previous work showing that DeltaNp73 is essential for survival of peripheral sympathetic neurons (Pozniak et al., 2000), indicate that p73 isoforms are essential survival proteins in CNS as well as PNS neurons, and that they likely play a role not only during developmental cell death but also in the long-term maintenance of at least some adult neurons. more...

Brain-derived neurotrophic factor (BDNF) is transported anterogradely in neurons of the CNS and can be released by activity-dependent mechanisms to regulate synaptic plasticity. However, few neural networks have been identified in which the production, transport, and effects of BDNF on postsynaptic neurons can be analyzed in detail. In this study, we have identified such a network. BDNF has been colocalized by immunocytochemistry with tyrosine hydroxylase (TH) in nerve fibers and nerve terminals within the lateral septum of rats. BDNF-containing nerve fibers terminate on a population of calbindin-containing neurons in lateral septum that contain TrkB, the high-affinity receptor for BDNF. Overexpression of BDNF in noradrenergic neurons increased levels of calbindin in septum, as well as in whole-brain lysates. Septal levels of calbindin and BDNF partially decreased after unilateral lesions of the medial forebrain bundle (MFB), induced with 6-hydroxydopamine, a treatment that abolished TH staining. These data suggest that BDNF is anterogradely transported within the MFB in catecholaminergic neurons arising from brainstem nuclei. To determine whether BDNF affects the production of calbindin in lateral septal neurons directly, we tested the effects of BDNF on cultures of septal neurons from embryonic day 16-17 rats. BDNF promoted the expression of calbindin, as well as the arborization of calbindin-containing neurons, but BDNF had no effect on cell division or survival. Together, these results suggest that BDNF, anterogradely transported in catecholaminergic neurons, regulates calbindin expression within the lateral septum. more...

The neurotrophin brain-derived neurotrophic factor (BDNF) has been implicated in the survival and differentiation of central nervous system neurons, including dopaminergic cells in culture. To determine whether BDNF might play a role in the development of dopaminergic neurons in vivo, we used a previously characterized transgenic mouse (DBH:BDNF) that overexpresses BDNF in adrenergic and noradrenergic neurons as a result of fusion of the BDNF gene to the dopamine beta-hydroxylase (DBH) gene promoter. We quantified dopaminergic neuronal profiles at four midbrain coronal levels and compared DBH:BDNF transgenic animals with wild-type mice of the same genetic background. Analysis of sections immunostained with tyrosine hydroxylase (TH) showed that the mean number of dopaminergic neurons in the four selected midbrain sections was 52% greater (one-way analysis of variance, P < 0.0005) in transgenic mice (2,165 +/- 55 S. E.M., n = 4) than in control mice (1,428 +/- 71 S.E.M., n = 4). The increase in dopaminergic neuron profile count in DBH:BDNF transgenic animals was confirmed by analysis of the pars compacta of the substantia nigra on Nissl-stained sections. Surface area of the reference region of interest containing TH-immunoreactive neurons was similar in transgenic and control mice. Regional analysis of different midbrain areas containing dopaminergic neurons suggested that the increase in cell profile count occurs in a relatively homogeneous manner. Comparison of TH-immunoreactive cell size showed a tendency for smaller neurons in transgenic animals, but the difference was not statistically significant. We conclude that DBH:BDNF transgenic mice show increased number of TH-immunoreactive cells in the midbrain. We propose that BDNF rescues dopaminergic neurons from the perinatal period of developmental cell death as a consequence of increased anterograde transport of the neurotrophin via the coeruleonigral projection., (Copyright 1999 Wiley-Liss, Inc.) more...

We study the neurogenesis of a distinct subclass of rat striatum gamma-aminobutyric acid (GABA)ergic interneurons marked by the calcium-binding protein parvalbumin (PV). Timed pregnant rats are given an intraperitoneal injection of bromodeoxyuridine (BrdU), a marker of cell proliferation, on designated days between embryonic day (E) 11 and E22. Birthdate of PV neurons is determined in the adult neostriatum and nucleus accumbens by using a BrdU-PV double-labeling immunohistochemical technique. PV-immunoreactive interneurons of the neostriatum show maximum birthrates (>10% double-labeling) between E14-E17, whereas PV-immunoreactive interneurons of the nucleus accumbens show maximum double-labeling between E16-E19. In the neostriatum, caudal PV-immunoreactive neurons are born before those at rostral levels, and lateral PV-immunoreactive neurons become postmitotic before medial neurons. In the postcommissural striatum, ventral PV-immunoreactive neurons become postmitotic before dorsal neurons. In the precommissural striatum, ventral neurons are born before dorsal neurons laterally, but a dorsoventral gradient is seen medially. At corresponding coronal levels, PV-immunoreactive neurons of the nucleus accumbens are born shortly after PV neurons of the neostriatum. Analysis of BrdU labeling intensity in the nucleus accumbens shows that medium spiny projection neurons of the shell become postmitotic before neurons of the core. Similarly, PV-immunoreactive interneurons of the nucleus accumbens shell are born before PV interneurons of the core. Compared with cholinergic interneurons of the neostriatum, PV-immunoreactive interneurons are born later, but neurogenetic gradients are similar. The period of striatum PV interneuron genesis encompasses the period for somatostatin interneurons, although the latter neurons do not show neurogenetic gradients, possibly due to heterogeneous subtypes. Consideration of basal telencephalon neurogenesis suggests that subpopulations of striatum interneurons may share common neurogenetic features with phenotypically similar populations in the basal forebrain, with final morphology and connectivity depending on local cues provided by the host environment. more...

The cortex projects heavily to the striatum and makes asymmetrical synaptic contact mainly with the spines of medium-sized densely spiny neurones. The possibility exists that corticostriatal terminals also make synaptic contact with classes of striatal interneurones. The primary objective of the present experiment was to determine whether parvalbumin-immunoreactive neurones, which represent a class of GABAergic interneurones in the striatum, also receive a direct synaptic input from corticostriatal fibres. The anterograde tracer biocytin was injected into the motor and premotor cortices of the squirrel monkey (Saimiri sciureus). Following perfuse-fixation, sections of the striatum were processed histochemically to reveal the transported biocytin using an avidin-biotin-peroxidase complex and diaminobenzidine as the chromogen. They were then immunostained to reveal parvalbumin using benzidine dihydrochloride as the chromogen. In both the light and electron microscopes, the morphological features and the afferent synaptic input of the parvalbumin-immunoreactive neurones were similar to those observed in other species. Similarly, the morphology and postsynaptic targets of the corticostriatal terminals were similar to those described in other species. Light microscopic examination revealed that the anterogradely labelled corticostriatal terminals were often in close apposition to the parvalbumin-positive neurones. At the electron microscopic level the biocytin-positive corticostriatal terminals were found to make asymmetrical synaptic contacts mainly with spines. The parvalbumin-positive neurones were seen to have an invaginated nucleus, extensive cytoplasm and relatively few spines. Parvalbumin-immunoreactive dendrites received a dense synaptic input consisting mainly of asymmetric synapses and only a few symmetric synapses. Biocytin-labelled corticostriatal terminals were often seen in asymmetrical synaptic contact with parvalbumin-immunoreactive dendrites. These results show that GABAergic interneurones identified on the basis of parvalbumin immunoreactivity, in addition to the projection neurones of the striatum, are under the direct influence of the cerebral cortex. more...