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International audience; Background: The 5XFAD model of Alzheimer’s disease (AD) bearing five familial mutations of Alzheimer’s disease on human APP and PSEN1 transgenes shows deposits of amyloid-β peptide (Aβ) as early as 2 months, while deficits in long-term memory can be detected at 4 months using the highly sensitive olfactory-dependent tests that we previously reported. Objective: Given that detecting early dysfunctions in AD prior to overt pathology is of major interest in the field, we sought to detect memory deficits at earlier stages of the disease in 3-month-old male 5XFAD mice. Methods: To this end, we used the Helico Maze, a behavioral task that was recently developed and patented. This device allows deeper analysis of learning and subcategories of hippocampal-dependent long-term memory using olfactory cues. Results: Eight male 5XFAD and 6 male wild-type (WT: C57Bl6 background) mice of 3 months of age were tested in the Helico Maze. The results demonstrated, for the first time, a starting deficit of pure reference long-term memory. Interestingly, memory impairment was clearly correlated with Aβ deposits in the hippocampus. While we also found significant differences in astrogliosis between 5XFAD and WT mice, this was not correlated with memory abilities. Conclusion: Our results underline the efficiency of this new olfactory-dependent behavioral task, which is easy to use, with a small cohort of mice. Using the Helico Maze may open new avenues to validate the efficacy of treatments that target early events related to the amyloid-dependent pathway of the disease and AD progression.

Stimulant use, including cocaine, often occurs in a social context whose influence is important to understand to decrease intake and reduce associated harms. Although the importance of social influence in the context of drug addiction is known, there is a need for studies assessing its neurobiological substrate and for translational research.Here, we explored the influence of peer presence and familiarity on cocaine intake and its neurobiological basis. Given the regulatory role of the subthalamic nucleus (STN) on cocaine intake and emotions, we investigated its role on such influence of social context on cocaine intake.We first compared cocaine consumption in various conditions (with no peer present or with peers with different characteristics: abstinent peer or drug-taking peer, familiar or not, cocaine-naive or not, dominant or subordinate) in rats (n = 90). Then, with a translational approach, we assessed the influence of the social context (alone, in the group, in a dyad with familiar or non-familiar peers) on drug intake in human drug users (n = 77).The drug consumption was reduced when a peer was present, abstinent, or drug-taking as well, and further diminished when the peer was non-familiar. The presence of a non-familiar and drug-naive peer represents key conditions to diminish cocaine intake. The STN lesion by itself reduced cocaine intake to the level reached in presence of a non-familiar naive peer and affected social cognition, positioning the STN as one neurobiological substrate of social influence on drug intake. Then, the human study confirmed the beneficial effect of social presence, especially of non-familiar peers.Our results indirectly support the use of social interventions and harm reduction strategies and position the STN as a key cerebral structure to mediate these effects.

Membrane-type matrix metalloproteinase 5 (MT5-MMP) deficiency in the 5xFAD mouse model of Alzheimer's disease (AD) reduces brain neuroinflammation and amyloidosis, and prevents deficits in synaptic activity and cognition in prodromal stages of the disease. In addition, MT5-MMP deficiency prevents interleukin-1 beta (IL-1β)-mediated inflammation in the peripheral nervous system. In this context, we hypothesized that the MT5-MMP/IL-1β tandem could regulate nascent AD pathogenic events in developing neural cells shortly after the onset of transgene activation.To test this hypothesis, we used 11-14 day in vitro primary cortical cultures from wild type, MT5-MMP5xFAD cells showed higher levels of MT5-MMP than wild type, concomitant with higher basal levels of inflammatory mediators. Moreover, MT5-MMP-deficient cultures had strong decrease of the inflammatory response to IL-1β, as well as decreased stability of recombinant IL-1β. The levels of amyloid beta peptide (Aβ) were similar in 5xFAD and wild-type cultures, and IL-1β treatment did not affect Aβ levels. Instead, the absence of MT5-MMP significantly reduced Aβ by more than 40% while sparing APP metabolism, suggesting altogether no functional crosstalk between IL-1β and APP/Aβ, as well as independent control of their levels by MT5-MMP. The lack of MT5-MMP strongly downregulated the AAV-induced neuronal accumulation of the C-terminal APP fragment, C99, and subsequently that of Aβ. Finally, MT5-MMP deficiency prevented basal hyperexcitability observed in 5xFAD neurons, but not hyperexcitability induced by IL-1β treatment.Neuroinflammation and hyperexcitability precede Aβ accumulation in developing neural cells with nascent expression of AD transgenes. MT5-MMP deletion is able to tune down basal neuronal inflammation and hyperexcitability, as well as APP/Aβ metabolism. In addition, MT5-MMP deficiency prevents IL-1β-mediated effects in brain cells, except hyperexcitability. Overall, this work reinforces the idea that MT5-MMP is at the crossroads of pathogenic AD pathways that are already incipiently activated in developing neural cells, and that targeting MT5-MMP opens interesting therapeutic prospects.

International audience; Parkinson's disease (PD) is a progressive neurodegenerative disease originating from the loss of dopa-mine (DA) neurons in the substantia nigra pars compacta (SNC). The small-conductance calcium-activated potassium (SK) channels play an essential role in the regulation of midbrain DA neuron activity patterns, as well as excitability of other types of neurons of the basal ganglia. We therefore questioned whether the SK channel expression in the basal ganglia is modified in parkinsonian rats and how this could impact behavioral performance in a reaction time task. We used a rat model of early PD in which the progressive nigrostriatal DA degeneration was produced by bilateral infusions of 6-hydroxydopamine (6-OHDA) into the striatum. In situ hybridization of SK2 and SK3 mRNA and binding of iodinated apamin (SK2/SK3 blocker) were performed at 1, 8 or 21 days postsurgery in sham and 6-OHDA lesion groups. A significant decrease of SK3 channel expression was found in the SNC of lesioned animals at the three time points, with no change of SK2 channel expression. Interestingly, an upregulation of SK2 mRNA and apamin binding was found in the subthalamic nucleus (STN) at 21 days postlesion. These results were confirmed using quantitative real time polymerase chain reaction (qRT-PCR) approach. Functionally, the local infusion of apamin into the STN of parkinsonian rats enhanced the akinetic deficits produced by nigrostriatal DA lesions in a reaction time task while apamin infusion into the SNC had an opposite effect. These effects disappear when the positive modulator of SK channels (CyPPA) is co-administered with apamin. These findings suggest that an upregulation of SK2 channels in the STN may underlie the physiological adjustment to increased subthalamic excitability following partial DA denervation.

Neural cell adhesion molecule (NCAM) is associated with polysialic acid (PSA), and its function is highly dependent on the extent of polysialylation through the activity of two polysialyltransferases, sialyltransferase-X (STX) and polysialyltransferase (PST). PSA-NCAM plays an important role in synaptic plasticity in the hippocampus. The involvement of STX and PST during mnesic processes was assessed in the adult rat hippocampus. We investigated whether different levels in learning and memory using an olfactory associative task influenced STX and PST gene expression in the hippocampus using semiquantitative transcription-polymerase chain reaction. Then, NCAM polysialylation and cell proliferation were quantified in the dentate gyrus of a "Learning and Memory" group using immunohistochemistry. We found that only the expression level of PST mRNA increased with learning performance and returned to an initial level when learned associations were consolidated in long-term memory, while STX mRNA levels remained unchanged. This phenomenon was accompanied by an increase in PSA on NCAM but not by cell proliferation in the dentate gyrus. Our results suggest a different involvement for STX and PST in neural plasticity: while STX is probably involved in the proliferation of neural progenitor cells, PST could play a key role in synaptic plasticity of mature neural networks. The expression of the STX and PST genes could, therefore, be useful markers of neurobiological plasticity in the brain, allowing to follow chronological events in limbic and cortical structures related first to learning and memory processes (for PST) and, second, to adult neurogenesis processes (for STX).

International audience; Neuronal plasticity and neurogenesis occur in the adult hippocampus and ă in other brain structures such as the olfactory bulb and often involve ă the neural cell adhesion molecule NCAM. During an olfactory associative ă discrimination learning task, NCAM polysialylation triggers neuronal ă plasticity in the adult hippocampus. The PST enzyme likely modulates ă this polysialylation, but not STX, a second sialyltransferase. How the ă two polysialyltransferases are involved in the adult olfactory bulb ă remains unknown. We addressed this question by investigating the effect ă of olfactory associative learning on plasticity and neurogenesis. After ă a hippocampo-dependent olfactory associative task learning, we measured ă the expression of both PST and STX polysialyltransferases in the ă olfactory bulbs of adult rats using quantitative PCR. In parallel, ă immunohistochemistry was used to evaluate both NCAM polysialylation ă level and newly-born cells, with or without learning. After learning, no ă changes were observed neither in the expression level of PST and NCAM ă polysialylation, nor in STX gene expression level and newly-born cells ă number in the olfactory bulb. (C) 2016 Elsevier Inc. All rights ă reserved.

The aim of this study was to determine the neurobiological bases of behavioral deficits associated with cholinergic damage and the potential of long-term environmental enrichment as a therapeutic agent. Rats were submitted to intra-structures injection of 192 IgG-saporin and then behaviorally tested 1 month and 1 year post-lesion in a nonmatching-to-position task. The gene expression changes were assessed by cDNA macroarray technology using the GE array Q series designed to profile the expression of neurotrophic signaling molecules. Results showed that (1) cholinergic injury modulated the expression of genes such as brain-derived neurotrophin factor but also genes associated with inflammatory response, neuron apoptosis, regulation of angiogenesis, and synaptic plasticity, (2) aging is associated with regulation of glial proliferation and apoptosis, and (3) long-term enriched environment housing enhanced behavioral performance in lesioned and non-lesioned rats and upregulated gene expression. This therapeutic role of the enriched environment seemed to be associated with a suppression of expression of genes involved in apoptosis, glial cell differentiation, and cell cycle, but also with an enhanced expression of a subset of genes involved in signal transduction.

Small interfering RNAs (siRNA) are double-stranded RNAs of 9-29 nucleotides designed to reduce the expression of homologous genes by a process known as RNA interference (RNAi). Most studies using siRNA in neurons have been performed in mammalian cell cultures. Only few reports have reported the effects of in vivo infusion of siRNA into the brain. In the present study, we performed local intracerebral infusions of naked siRNA against glutamic acid decarboxylase 67 (GAD67) mRNA to engineer specific knock-down of GAD67 protein in the striatum of adult rats. Directly injecting a mix of GAD67 siRNAs into the striatum decreased the levels of corresponding mRNA, evaluated by quantitative real-time PCR. In particular, we show that GAD67 mRNA expression is reduced in the striatum for 3, 6, and 24h following intrastriatal injection of GAD67 siRNA and is restored at 72h. Relative to controls, the levels of GAD67 protein were also lower in the striatum for 6 and 24h after injection. No changes in GAD65 expression, one of the two isoforms of GAD, were detected in the striatum, which further validates the specificity of the siRNA. We demonstrate the efficiency of the RNAi strategy for producing a specific and selective down-regulation of GAD67 in the adult rat brain. This suggests that siRNA-mediated gene knock-down constitute a valid methodological approach for studying the functional consequences of a transient decrease of a gene expression in a brain structure.

Voltage-gated potassium channels (Kv) are critically involved in learning and memory processes. It is not known, however, whether the expression of the Kv1.1 subunit, constituting Kv1 channels, can be specifically regulated in brain areas important for learning and memory processing. Radioactive in situ hybridization was used to evaluate the content of Kv1.1 α-subunit mRNA in the olfactory bulb, ventral, and dorsal hippocampus at different stages of an odor-discrimination associative task in rats. Naive, conditioned, and pseudoconditioned animals were sacrificed at different times either prior to a two-odor significance learning or after odor discrimination was established. Important decreases of Kv1.1 mRNA levels were transiently observed in the ventral hippocampus before successful learning when compared with the pseudoconditioned group. Moreover, temporal group analysis showed significant labeling alterations in the hippocampus of conditioned and pseudoconditioned groups throughout the training. Finally, Kv1.1 mRNA levels in the hippocampus were positively correlated with odor-reward association learning in rats that were beginning to discriminate between odors. These findings indicate that the Kv1.1 subunit is transiently down-regulated in the early stages of learning and suggest that Kv1 channel expression regulation is critical for the modification of neuronal substrates underlying new information acquisition.

Molecular determinants of excitability were studied in pure cultures of rat embryonic motoneurons. Using RT-PCR, we have shown here that the spike-generating Na(+) current is supported by Nav1.2 and/or Nav1.3 alpha-subunits. Nav1.1 and Nav1.6 transcripts were also identified. We have demonstrated that alternatively spliced isoforms of Nav1.1 and Nav1.6, resulting in truncated proteins, were predominant during the first week in culture. However, Nav1.6 protein could be detected after 12 days in vitro. The Nav beta 2.1 transcript was not detected, whereas the Nav beta 1.1 transcript was present. Even in the absence of Nav beta 2.1, alpha-subunits were correctly inserted into the initial segment. RT-PCR (at semi-quantitative and single-cell levels) and immunocytochemistry showed that transient K(+) currents result from the expression of Kv4.2 and Kv4.3 subunits. This is the first identification of subunits responsible for a transient K(+) current in spinal motoneurons. The blockage of Kv4.2/Kv4.3 using a specific toxin modified the shape of the action potential demonstrating the involvement of these conductance channels in regulating spike repolarization and the discharge frequency. Among the other Kv alpha-subunits (Kv1.3, 1.4, 1.6, 2.1, 3.1 and 3.3), we showed that the Kv1.6 subunit was partly responsible for the sustained K(+) current. In conclusion, this study has established the first correlation between the molecular nature of voltage-dependent Na(+) and K(+) channels expressed in embryonic rat motoneurons in culture and their electrophysiological characteristics in the period when excitability appears.

Neural cell adhesion molecule (NCAM) is associated with polysialic acid (PSA), and its function is highly dependent on the extent of polysialylation through the activity of two polysialyltransferases, sialyltransferase-X (STX) and polysialyltransferase (PST). PSA-NCAM plays an important role in synaptic plasticity in the hippocampus. The involvement of STX and PST during mnesic processes was assessed in the adult rat hippocampus. We investigated whether different levels in learning and memory using an olfactory associative task influenced STX and PST gene expression in the hippocampus using semiquantitative transcription-polymerase chain reaction. Then, NCAM polysialylation and cell proliferation were quantified in the dentate gyrus of a "Learning and Memory" group using immunohistochemistry. We found that only the expression level of PST mRNA increased with learning performance and returned to an initial level when learned associations were consolidated in long-term memory, while STX mRNA levels remained unchanged. This phenomenon was accompanied by an increase in PSA on NCAM but not by cell proliferation in the dentate gyrus. Our results suggest a different involvement for STX and PST in neural plasticity: while STX is probably involved in the proliferation of neural progenitor cells, PST could play a key role in synaptic plasticity of mature neural networks. The expression of the STX and PST genes could, therefore, be useful markers of neurobiological plasticity in the brain, allowing to follow chronological events in limbic and cortical structures related first to learning and memory processes (for PST) and, second, to adult neurogenesis processes (for STX).

Methylene blue (MB) belongs to the phenothiazinium family. It has been used to treat a variety of human conditions and has beneficial effects on the central nervous system in rodents with and without brain alteration. The present study was designed to test whether chronic MB treatment taken after (therapeutic effect) or before (preventive effect) the onset of beta-amyloid pathology influences cognition in a transgenic mouse model (APP/PS1). In addition, the present study aims at revealing whether these behavioral effects might be related to brain alteration in beta-amyloid deposition. To this end, we conducted an in vivo study and compared two routes of drug administration, drinking water versus intraperitoneal injection. Results showed that transgenic mice treated with MB orally or following intraperitoneal injection were protected from cognitive impairments in a variety of social, learning, and exploratory tasks. Immunoreactive beta-amyloid deposition was significantly reduced in the hippocampus and adjacent cortex in MB-treated transgenic mice. Interestingly, these beneficial effects were observed independently of beta-amyloid load at the time of MB treatment. This suggests that MB treatment is beneficial at both therapeutic and preventive levels. Using solid-state High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HRMAS-NMR), we showed that MB administration after the onset of amyloid pathology significantly restored the concentration of two metabolites related to mitochondrial metabolism, namely alanine and lactate. We conclude that MB might be useful for the therapy and prevention of Alzheimer's disease. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

A number of putative transcription factors described in the pituitary have been implicated as key elements in the processes that direct pituitary development. Three recently described proteins, Ptx1, Ptx2, and Ptx3, define a new family of transcription factors, the Ptx subfamily, within the paired-like class of homeodomain factors. In mice, Ptx1 and Ptx2 gene expression has been detected in the area of the pituitary primordium and is maintained throughout development in Rathke pouch and adult pituitary. In the present study, the expression of the Ptx1, Ptx2, and Ptx3 genes was characterized in the normal human pituitary and in the different types of human pituitary adenomas. Although no Ptx3 gene expression could be detected in these tissues, Ptx1 presented with a quite ubiquitous pattern of distribution, being expressed at quite constant levels in normal tissues and in all 60 pituitary tumors analyzed. The pattern of expression of the Ptx2 gene among the different subsets of pituitary adenomas was even more varied. No Ptx2 expression could be detected in corticotroph tumors. In contrast, high levels of Ptx2 messenger ribonucleic acid were measured in the gonadotroph tumors, although no specific correlation to other markers of the gonadotroph lineage differentiation, such as alphaGsu, LHbeta, or FSHbeta, could be evidenced. Finally, Ptx2 was also expressed in pure lactotroph adenomas and not in somatotroph adenomas. Ptx2 is, therefore, the first paired homeodomain pituitary transcription factor differentially expressed in these two lineages, which derive from a common precursor. These results support a role for Ptx2 in the terminal differentiation of somatotroph and lactotroph cell phenotypes.

International audience; Kv4 channels regulate the backpropagation of action potentials (b-AP) and have been implicated in the modulation of longterm potentiation (LTP). Here we showed that blockade of Kv4 channels by the scorpion toxin AmmTX3 impaired reference memory in a radial maze task. In vivo, AmmTX3 intracerebroventricular (i.c.v.) infusion increased and stabilized the EPSP-spike (E-S) component of LTP in the dentate gyrus (DG), with no effect on basal transmission or short-term plasticity. This increase in E-S potentiation duration could result from the combination of an increase in excitability of DG granular cells with a reduction of GABAergic inhibition, leading to a strong reduction of input specificity. Radioactive in situ hybridization (ISH) was used to evaluate the amounts of Kv4.2 and Kv4.3 mRNA in brain structures at different stages of a spatial learning task in naive, pseudoconditioned, and conditioned rats. Significant differences in Kv4.2 and Kv4.3 mRNA levels were observed between conditioned and pseudoconditioned rats. Kv4.2 and Kv4.3 mRNA levels were transiently up-regulated in the striatum, nucleus accumbens, retrosplenial, and cingulate cortices during early stages of learning, suggesting an involvement in the switch from egocentric to allocentric strategies. Spatial learning performance was positively correlated with the levels of Kv4.2 and Kv4.3 mRNAs in several of these brain structures. Altogether our findings suggestthat Kv4 channels could increase the signal-to-noise ratio during information acquisition, thereby allowing a better encoding of the memory trace.

Anorexia nervosa is a growing concern in mental health, often inducing death. The potential neuronal deficits that may underlie abnormal inhibitions of food intake, however, remain largely unexplored. We hypothesized that anorexia may involve altered signaling events within the nucleus accumbens (NAc), a brain structure involved in reward. We show here that direct stimulation of serotonin (5-hydroxytryptamine, 5-HT) 4 receptors (5-HT 4 R) in the NAc reduces the physiological drive to eat and increases CART (cocaine- and amphetamine-regulated transcript) mRNA levels in fed and food-deprived mice. It further shows that injecting 5-HT 4 R antagonist or siRNA-mediated 5-HT 4 R knockdown into the NAc induced hyperphagia only in fed mice. This hyperphagia was not associated with changes in CART mRNA expression in the NAc in fed and food-deprived mice. Results include that 5-HT 4 R control CART mRNA expression into the NAc via a cAMP/PKA signaling pathway. Considering that CART may interfere with food- and drug-related rewards, we tested whether the appetite suppressant properties of 3,4- N -methylenedioxymethamphetamine (MDMA, ecstasy) involve the 5-HT 4 R. Using 5-HT 4 R knockout mice, we demonstrate that 5-HT 4 R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART mRNA expression in the NAc. Directly injecting CART peptide or CART siRNA into the NAc reduces or increases food consumption, respectively. Finally, stimulating 5-HT 4 R- and MDMA-induced anorexia were both reduced by injecting CART siRNA into the NAc. Collectively, these results demonstrate that 5-HT 4 R-mediated up-regulation of CART in the NAc triggers the appetite-suppressant effects of ecstasy.

This study examined the effects of prolonged (4 days) high frequency stimulation (HFS) of the subthalamic nucleus (STN), in comparison with those of STN lesion, on the dopamine denervation-mediated cellular changes in the basal ganglia in a Wistar rat model of Parkinson's disease. STN HFS counteracted the dopamine lesion-induced increase in GAD67 mRNA expression in the output structures of the basal ganglia, as shown previously after STN lesion, providing cellular support for the similar antiparkinsonian benefits produced by the two surgical procedures. The dopamine denervation-induced increase in GAD67 mRNA levels in the globus pallidus was partially antagonized after HFS and totally reversed after ibotenate-induced STN lesion. The overexpression of striatal enkephalin mRNA tended to be further increased by HFS but was antagonized by STN lesion. The decrease in striatal substance P mRNA levels was affected neither by STN HFS nor lesion. As STN HFS for two hours was previously found not to interfere with the effects of dopamine lesion in the globus pallidus and striatum, the present data provide strong evidence that the effects of STN surgery in these structures involve long-term adaptive processes and that the rearrangements mediated by HFS and lesion are, at least in part, different.

The subthalamic nucleus (STN) is now recognized as the main anatomical target for the surgical treatment of advanced Parkinson’s disease (PD) by the high frequency stimulation (HFS) procedure. The rationale for targeting the STN for neurosurgery in PD patients came from experimental evidence showing that the loss of dopaminergic nigrostriatal neurons in PD leads, through complex changes in cellular interactions in the basal ganglia circuitry, to changes in the firing rate and pattern of STN neurons and to increased metabolic activity, suggesting overactivity of this nucleus (Miller and Delong, 1987; Hollerman and Grace, 1992; Bergman et al., 1994; Hassani et al., 1996; Vila et al., 2000). Abnormal activity of the STN, which sends presumably glutamatergic excitatory projections to the basal ganglia output structures, represented by the substantia nigra pars reticulata (SNr) and the internal globus pallidus (GPi) also termed entopeduncular nucleus (EP), has been therefore thought to play a pivotal role in the expression of PD symptoms. Accordingly, lesioning the STN has been reported to normalize the metabolic activity as well as the firing rate and pattern of neurons in the SNr and EP (Blandini et al., 1997; Burbaud et al., 1995), to prevent the changes in gene expression resulting from dopamine denervation in basal ganglia structures (Delfs et al., 1995), and to alleviate parkinsonian motor deficits (Bergman et al., 1990; Aziz et al., 1991; Alvarez et al., 2001). HFS has been developed in the last twenty years as an alternative to the lesion

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is now recognized as an effective treatment for advanced Parkinson's disease, but the molecular basis of its effects remains unknown. This study examined the effects of unilateral STN HFS (2 hr of continuous stimulation) in intact and hemiparkinsonian awake rats on STN neuron metabolic activity and on neurotransmitter-related gene expression in the basal ganglia, by means of in situ hybridization histochemistry and immunocytochemistry. In both intact and hemiparkinsonian rats, this stimulation was found to induce c-fos protein expression but to decrease cytochrome oxidase subunit I mRNA levels in STN neurons. STN HFS did not affect the dopamine lesion-mediated overexpression of enkephalin mRNA or the decrease in substance P in the ipsilateral striatum. The lesion-induced increases in intraneuronal glutamate decarboxylase 67 kDa isoform (GAD67) mRNA levels on the lesion side were reversed by STN HFS in the substantia nigra, partially antagonized in the entopeduncular nucleus but unaffected in the globus pallidus. The stimulation did not affect neuropeptide or GAD67 mRNA levels in the side contralateral to the dopamine lesion or in intact animals. These data furnish the first evidence that STN HFS decreases the metabolic activity of STN neurons and antagonizes dopamine lesion-mediated cellular defects in the basal ganglia output structures. They provide molecular substrate to the therapeutic effects of this stimulation consistent with the current hypothesis that HFS blocks STN neuron activity. However, the differential impact of STN HFS on the effects of dopamine lesion among structures receiving direct STN inputs suggests that this stimulation may not cause simply interruption of STN outflow.

Background Unilateral vestibular deafferentation results in strong microglial and astroglial activation in the vestibular nuclei (VN) that could be due to an inflammatory response. This study was aimed at determining if markers of inflammation are upregulated in the VN after chemical unilateral labyrinthectomy (UL) in the rat, and if the inflammatory response, if any, induces the expression of neuroprotective factors that could promote the plasticity mechanisms involved in the vestibular compensation process. The expressions of inflammatory and neuroprotective factors after chemical or mechanical UL were also compared to verify that the inflammatory response was not due to the toxicity of sodium arsanilate. Methods Immunohistological investigations combined the labeling of tumor necrosis factor α (TNFα), as a marker of the VN inflammatory response, and of nuclear transcription factor κB (NFκB) and manganese superoxide dismutase (MnSOD), as markers of neuroprotection that could be expressed in the VN because of inflammation. Immunoreactivity (Ir) of the VN cells was quantified in the VN complex of rats. Behavioral investigations were performed to assess the functional recovery process, including both static (support surface) and dynamic (air-righting and landing reflexes) postural tests. Results Chemical UL (arsanilate transtympanic injection) induced a significant increase in the number of TNFα-Ir cells in the medial and inferior VN on both sides. These changes were detectable as early as 4 h after vestibular lesion, persisted at 1 day, and regained nearly normal values at 3 days. The early increase in TNFα expression was followed by a slightly delayed upregulation of NFκB 8 h after chemical UL, peaking at 1 day, and regaining control values 3 days later. By contrast, upregulation of MnSOD was more strongly delayed (1 day), with a peak at 3 days, and a return to control values at 15 days. Similar changes of TNFα, NFκB, and MnSOD expression were found in rats submitted to mechanical UL. Behavioral observations showed strong posturo-locomotor deficits early after chemical UL (1 day) and a complete functional recovery 6 weeks later. Conclusions Our results suggest that the upregulation of inflammatory and neuroprotective factors after vestibular deafferentation in the VN may constitute a favorable neuronal environment for the vestibular compensation process.