Contralateral Striatum Research Articles

Neurturin protects against 6-hydroxydopamine-induced reductions in evoked dopamine overflow in rat striatum

Neurturin (NTN), a member of the glial cell line-derived neurotrophic factor (GDNF) family, has substantial effects on normal and lesioned nigrostriatal dopamine systems. However, its ability to protect against toxin-induced loss of striatal dopamine release has not been previously reported. The goal of the present study was to determine if NTN could protect against 6-hydroxydopamine (6-OHDA)-induced reductions in striatal dopamine overflow and tissue levels of dopamine and to compare the effects of NTN with those of GDNF. Male Fischer-344 rats were given a single injection of vehicle, or 5μg NTN or GDNF, into the right striatum. The following day the animals were given a single injection of 12μg 6-OHDA into the striatum at the same site where the trophic factor was injected. Microdialysis experiments conducted three weeks later indicated that the 6-OHDA decreased basal levels of dopamine and metabolites in the lesioned striatum compared to the contralateral striatum, and NTN was able to partially protect against the 6-OHDA-induced reductions. Injection of NTN one day prior to 6-OHDA also led to significant protection against loss of both potassium- and amphetamine-evoked overflow of dopamine. The NTN treatments partially protected against 6-OHDA-induced reductions in striatal tissue levels of dopamine and completely protected against loss of nigral dopamine content. The protective effects of NTN were similar in magnitude to those of GDNF. These results support that within the experimental parameters used in this study, NTN is as effective as GDNF in protecting against the dopamine-depleting effects of intrastriatal 6-OHDA.

Intravenous treatment of experimental Parkinson's disease in the mouse with an IgG-GDNF fusion protein that penetrates the blood–brain barrier

Glial-derived neurotrophic factor (GDNF) is a trophic factor for the nigra-striatal tract in experimental Parkinson's disease (PD). The neurotrophin must be administered by intra-cerebral injection, because GDNF does not cross the blood–brain barrier (BBB). In the present study, GDNF was re-engineered to enable receptor-mediated transport across the BBB following fusion of GDNF to the heavy chain of a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-GDNF. This fusion protein had been previously shown to retain low nM binding constants for both the GDNF receptor and the mouse TfR, and to rapidly enter the mouse brain in vivo following intravenous administration. Experimental PD in mice was induced by the intra-striatal injection of 6-hydroxydopamine, and mice were treated with either saline or the cTfRMAb-GDNF fusion protein every other day for 3 weeks, starting 1 h after toxin injection. Fusion protein treatment caused a 44% decrease in apomorphine-induced rotation, a 45% reduction in amphetamine-induced rotation, a 121% increase in the vibrissae-elicited forelimb placing test, and a 272% increase in striatal tyrosine hydroxylase (TH) enzyme activity at 3 weeks after toxin injection. Fusion protein treatment caused no change in TH enzyme activity in either the contralateral striatum or the frontal cortex. In conclusion, following fusion of GDNF to a BBB molecular Trojan horse, GDNF trophic effects in brain in experimental PD are observed following intravenous administration.

Iron regulatory protein-2 knockout increases perihematomal ferritin expression and cell viability after intracerebral hemorrhage

Iron is deposited in perihematomal tissue after an intracerebral hemorrhage (ICH), and may contribute to oxidative injury. Cell culture studies have demonstrated that enhancing ferritin expression by targeting iron regulatory protein (IRP) binding activity reduces cellular vulnerability to iron and hemoglobin. In order to assess the therapeutic potential of this approach after striatal ICH, the effect of IRP1 or IRP2 gene knockout on ferritin expression and injury was quantified. Striatal ferritin in IRP1 knockout mice was similar to that in wild-type controls 3 days after stereotactic injection of artificial CSF or autologous blood. Corresponding levels in IRP2 knockouts were increased by 11-fold and 8.4-fold, respectively, compared with wild-type. Protein carbonylation, a sensitive marker of hemoglobin neurotoxicity, was increased by 2.4-fold in blood-injected wild-type striata, was not altered by IRP1 knockout, but was reduced by approximately 60% by IRP2 knockout. Perihematomal cell viability in wild-type mice, assessed by MTT assay, was approximately half of that in contralateral striata at 3 days, and was significantly increased in IRP2 knockouts but not in IRP1 knockouts. Protection was also observed when hemorrhage was induced by collagenase injection. These results suggest that IRP2 binding activity reduces ferritin expression in the striatum after ICH, preventing an optimal response to elevated local iron concentrations. IRP2 binding activity may be a novel therapeutic target after hemorrhagic CNS injuries.

Rehabilitation after intracerebral hemorrhage in rats improves recovery with enhanced dendritic complexity but no effect on cell proliferation

Rehabilitation, consisting of enriched environment and skilled reach training, improves recovery after intracerebral hemorrhage (ICH) in rats. We tested whether rehabilitation influences dendritic morphology (Golgi–Cox staining—experiment 1) or cell proliferation (immunohistochemistry—experiment 2). In the latter experiment, BrdU was given from 14 to 18 days post stroke, and cells were labeled for BrdU along with NeuN, Iba1 or GFAP. One week after a striatal ICH, via collagenase infusion, the rats were given rehabilitation for 2 weeks or control treatment (group housing in standard cages). Behavioral outcome (e.g., skilled reaching, walking) was assessed at multiple times. Rats were euthanized at 5 (experiment 2) or 6 (experiment 1) weeks post-ICH. As expected, rehabilitation significantly improved skilled reaching and walking ability. There was also a concomitant increase in dendritic length in peri-hematoma striatum and ipsilateral cortex as well as in the contralateral striatum. Lesion volume did not differ between groups, nor did cell proliferation. There was no evidence of neurogenesis, but there was increased Iba1 and GFAP labeling in the injured hemisphere. Thus, rehabilitation likely improves outcome after ICH though a plasticity response (e.g., increased dendritic growth) that does not involve neurogenesis.

Abnormal expression of dopamine and serotonin transporters associated with the pathophysiologic mechanism of Tourette syndrome

Tourette syndrome (TS) is a neurobehavioral and neuropsychiatric disorder and its pathophysiology is not well understood. However, recent studies provide evidence implicating metabolic abnormalities of dopamine (DA) and serotonin (5-HT) of the basal ganglia both in TS patients and TS animal models. It is also well known that dopamine and serotonin transporters (DAT and SERT) are monoamine neurotransmitter transporters, which participate in the metabolism of DA and 5-HT, respectively. To evaluate whether expression of DAT and SERT in the striatum could lead to pathophysiological change in TS rat model. Twenty-four Wistar male rats were randomly allocated to: TS model group (n=12) and control group (n=12). The stereotypy counts were recorded during the 2-week period of inducing TS rat models. The levels of DA and 5-HT in striatum homogenate were measured by ELISA. The protein and mRNA expression of DAT and SERT in the striatum were tested respectively by Immunofluorescence, Western blot and quantitative real-time PCR. Results : ANOVA analysis indicated that the stereotypy scores were much higher in the TS model group than in the control group at different time points (P<0.01). By ELISA analysis, the DA concentration in striatum homogenate was higher in the TS model group (130.92 +/- 25.60 ng/mL) than in the control group (101.00 +/- 20.14 ng/mL) (P<0.01), but 5-HT concentration in striatum was found to be lower in the TS model group (59.79 +/- 14.73 ng/mL) compared to the control group (77.01 +/- 14.05 ng/mL) (P<0.05). Analysis of protein and mRNA levels revealed a lower expression of DAT, concomitant with a higher expression of SERT in striatum of the TS model group than in the control group. Lower expression in DAT, concomitant with higher expression in SERT could participate in the pathophysiology of TS.

Kindling as a model of temporal lobe epilepsy induces bilateral changes in spontaneous striatal activity

Basal ganglia are engaged in seizure propagation, control of seizures, and in epilepsy-induced neuroplasticity. Here, we tested the hypothesis that previously observed histological and neurochemical changes in the striatum of amygdala-kindled rats as a model of temporal lobe epilepsy are reflected in alterations of spontaneous striatal firing rates and patterns. Because experimental histological and clinical imaging studies indicated a bilateral involvement of the striatum in epilepsy-induced neuroplasticity, in vivo single-unit recordings were done bilaterally 1 day after a kindled seizure in rats kindled via the right amygdala. Compared to control animals, we observed (1) an increased irregularity of firing of neurons classified as striatal projection neurons and located in the anterior striatum ipsilateral to the kindling side and (2) an increased spontaneous activity of neurons classified as striatal projection neurons and located in the anterior striatum contralateral to the kindling side. These hyperactive neurons were located within the dorsolateral (sensorimotor) subregion of the striatum. The present study represents the first evidence of kindling-induced bilateral changes in electrophysiological properties of striatal neurons and demonstrates that the striatum is strongly affected by the functional reorganization of neurocircuits associated with kindling. The changes are probably caused by a combination of several factors including disturbed bilateral limbic and neocortical input as well as disturbed intrastriatal GABAergic function. The changes reflect a pathophysiological state predisposing the brain to epileptic discharge propagation or else (contralateral striatum) could represent a compensatory network of inhibitory circuits activated to prevent the propagation of seizure activity. The findings are relevant for a better understanding of kindling-induced network changes and might provide new targets for therapeutic manipulations in epilepsies.

Protective Effects of Neurotrophic Factor–Secreting Cells in a 6-OHDA Rat Model of Parkinson Disease

Stem cell-based therapy is a promising treatment for neurodegenerative diseases. In our laboratory, a novel protocol has been developed to induce bone marrow-derived mesenchymal stem cells (MSC) into neurotrophic factors- secreting cells (NTF-SC), thus combining stem cell-based therapy with the NTF-based neuroprotection. These cells produce and secrete factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor. Conditioned medium of the NTF-SC that was applied to a neuroblastoma cell line (SH-SY5Y) 1 h before exposure to the neurotoxin 6-hydroxydopamine (6-OHDA) demonstrated marked protection. An efficacy study was conducted on the 6-OHDA-induced lesion, a rat model of Parkinson's disease. The cells, either MSC or NTF-SC, were transplanted on the day of 6-OHDA administration and amphetamine-induced rotations were measured as a primary behavior index. We demonstrated that when transplanted posterior to the 6-OHDA lesion, the NTF-SC ameliorated amphetamine-induced rotations by 45%. HPLC analysis demonstrated that 6-OHDA induced dopamine depletion to a level of 21% compared to the untreated striatum. NTF-SC inhibited dopamine depletion to a level of 72% of the contralateral striatum. Moreover, an MRI study conducted with iron-labeled cells, followed by histological verification, revealed that the engrafted cells migrated toward the lesion. In a histological assessment, we found that the cells induced regeneration in the damaged striatal dopaminergic nerve terminal network. We therefore conclude that the induced MSC have a therapeutic potential for neurodegenerative processes and diseases, both by the NTFs secretion and by the migratory trait toward the diseased tissue.

Kinetics of Microglial Activation and Degeneration of Dopamine-Containing Neurons in a Rat Model of Parkinson Disease Induced by 6-Hydroxydopamine

In both Parkinson disease and in animal models of Parkinson disease, there is a microglial reaction in addition to the loss of dopaminergic neurons in the ventral midbrain. To determine the pathological role of this microglial reaction, we analyzed the kinetics of microglial activation and dopaminergic cell death induced in rats with the neurotoxin 6-hydroxydopamine. As early as Day 1 after the injection, there was a decline in the motor performance of the 6-hydroxydopamine-lesioned rats that correlated with a reduction of dopaminergic innervation of the contralateral striatum. Loss of dopaminergic neurons in the ventral midbrain developed a few days later and seemed to follow a specific temporospatial pattern. Degenerating neurons and activated microglia were seen only in areas in which dopaminergic cells were no longer observed, suggesting that the loss of the dopaminergic phenotype preceded the degenerative process. In sham-lesioned rats, there was a transient activation of microglia in the vicinity of the needle tract without any cell degeneration. This chronology of events supports the hypothesis that microglial activation is a secondary rather than primary phenomenon in dopaminergic cell degeneration induced by 6-hydroxydopamine.

Cerebral Ischemia–Reperfusion Injury in Rats—A 3 T MRI Study on Biphasic Blood–Brain Barrier Opening and the Dynamics of Edema Formation

Serial magnetic resonance imaging (MRI) was performed to investigate the temporal and spatial relationship between the biphasic nature of blood-brain barrier (BBB) opening and, in parallel, edema formation after ischemia-reperfusion (I/R) injury in rats. T(2)-weighted imaging combined with T(2)-relaxometry, mainly for edema assessment, was performed at 1 h after ischemia, after reperfusion, and at 4, 24 and 48 h after reperfusion. T(1)-weighted imaging was performed before and after gadolinium contrast at the last three time points to assess BBB integrity. The biphasic course of BBB opening with a significant reduction in BBB permeability at 24 h after reperfusion, associated with a progressive expansion of leaky BBB volume, was accompanied by a peak ipsilateral edema formation. In addition, at 4 h after reperfusion, edema formation could also be detected at the contralateral striatum as determined by the elevated T(2)-values that persisted to varying degrees, indicative of widespread effects of I/R injury. The observations of this study may indicate a dynamic temporal shift in the mechanisms responsible for biphasic BBB permeability changes, with complex relations to edema formation. Stroke therapy aimed at vasogenic edema and drug delivery for neuroprotection may also be guided according to the functional status of the BBB, and these findings have to be confirmed in human stroke.

Use of a single [123I]-FP-CIT SPECT to predict the severity of clinical symptoms of Parkinson disease

The aim of this study was to assess the ability of a single SPECT performed in the early stage of Parkinson's disease (PD) to predict disease severity in 19 patients with early PD. [(123)I]-FP-CIT striatal uptake was expressed as a ratio of specific:nonspecific uptake for defined brain areas. Clinical severity was determined by the UPDRS at baseline and 12-15 months following the SPECT procedure. [(123)I]-FP-CIT uptake in the contralateral putamen and striatum was correlated with UPDRS score at baseline, with a more significant correlation after 1-year interval. [(123)I]-FP-CIT uptake in all areas was correlated with bradykinesia and rigidity subscores only at follow up visit. Significant correlations were found between [(123)I]-FP-CIT uptake in the contralateral striatum, putamen and caudate and the difference between motor scores of 1-year interval (DeltaUPDRS). These results suggest that disease severity might be anticipated by a single SPECT at an early stage of the disease.

Bilateral effects of unilateral GDNF administration on dopamine- and GABA-regulating proteins in the rat nigrostriatal system

Dopamine (DA) affects GABA neuronal function in the striatum and together these neurotransmitters play a large role in locomotor function. We recently reported that unilateral striatal administration of GDNF, a growth factor that has neurotrophic effects on DA neurons and enhances DA release, bilaterally increased striatal neuron activity related to locomotion in aged rats. We hypothesized that the GDNF enhancement of DA function and resulting bilateral enhancement of striatal neuronal activity was due to prolonged bilateral changes in DA- and GABA-regulating proteins. Therefore in these studies we assessed dopamine- and GABA-regulating proteins in the striatum and substantia nigra (SN) of 24 month old Fischer 344 rats, 30 days after a single unilateral striatal delivery of GDNF. The nigrostriatal proteins investigated were the DA transporter (DAT), tyrosine hydroxylase (TH), and TH phosphorylation and were examined by blot-immunolabeling. The striatal GABA neuron-related proteins were examined by assay of the DA D 1 receptor, DARPP-32, DARPP-32 Thr 34 phosphorylation, and glutamic acid decarboxylase (GAD). Bilateral effects of GDNF on TH and DAT occurred only in the SN, as 30 μg GDNF increased ser19 phosphorylation, and 100 μg GDNF decreased DAT and TH protein levels. GDNF also produced bilateral changes in GAD protein in the striatum. A decrease in DARPP-32 occurred in the ipsilateral striatum, while increased D 1 receptor and DARPP-32 phosphorylation occurred in the contralateral striatum. The 30 μg GDNF infusion into the lateral striatum was confined to the ipsilateral striatum and substantia nigra. Thus, long-lasting bilateral effects of GDNF on proteins regulating DA and GABA neuronal function likely alter physiological properties in neurons, some with bilateral projections, associated with locomotion. Enhanced nigrostriatal excitability and DA release by GDNF may trigger these bilateral effects.

Hemichorea—hemiballismus associated with nonketotic hyperglycemia: A possible role of inflammation

Three cases of hemichorea–hemiballismus (HC–HB) associated with nonketotic hyperglycemia were reported. Of them two patients presented as HC–HB and the remaining one as generalized chorea-ballismus (CB). Brain MRI showed characteristic T1-weighted high-intensity lesions in the contralateral or bilateral striatum without edema or mass effect. They all had a prior history of respiratory or urinary infection. Cerebrospinal fluid test in two patients showed an elevation of protein concentration with normal cell and an increased IgG content and elevated IgG index or 24 h IgG intrathecal synthesis rate. These results suggested that inflammation within the central nervous system may participate in the pathogenesis of chorea and ballismus induced by NKH.

Cholinesterase inhibition and acetylcholine accumulation following intracerebral administration of paraoxon in rats

We evaluated the inhibition of striatal cholinesterase activity following intracerebral administration of paraoxon assaying activity either in tissue homogenates ex vivo or by substrate hydrolysis in situ. Artificial cerebrospinal fluid (aCSF) or paraoxon in aCSF was infused unilaterally (0.5 μl/min for 2 h) and ipsilateral and contralateral striata were harvested for ChE assay ex vivo. High paraoxon concentrations were needed to inhibit ipsilateral striatal cholinesterase activity (no inhibition at < 0.1 mM; 27% at 0.1 mM; 79% at 1 mM paraoxon). With 3 mM paraoxon infusion, substantial ChE inhibition was also noted in contralateral striatum. ChE histochemistry generally confirmed these concentration- and side-dependent effects. Microdialysates collected for up to 4 h after paraoxon infusion inhibited ChE activity when added to striatal homogenate, suggesting prolonged efflux of paraoxon. Since paraoxon efflux could complicate acetylcholine analysis, we evaluated the effects of paraoxon (0, 0.03, 0.1, 1, 10 or 100 μM, 1.5 μl/min for 45 min) administered by reverse dialysis through a microdialysis probe. ChE activity was then monitored in situ by perfusing the colorimetric substrate acetylthiocholine through the same probe and measuring product (thiocholine) in dialysates. Concentration-dependent inhibition was noted but reached a plateau of about 70% at 1 μM and higher concentrations. Striatal acetylcholine was below the detection limit at all times with 0.1 μM paraoxon but was transiently elevated (0.5–1.5 h) with 10 μM paraoxon. In vivo paraoxon (0.4 mg/kg, sc) in adult rats elicited about 90% striatal ChE inhibition measured ex vivo, but only about 10% inhibition measured in situ. Histochemical analyses revealed intense AChE and glial fibrillary acidic protein staining near the cannula track, suggesting proliferation of inflammatory cells/glia. The findings suggest that ex vivo and in situ cholinesterase assays can provide very different views into enzyme–inhibitor interactions. Furthermore, the proliferation/migration of cells containing high amounts of cholinesterase just adjacent to a dialysis probe could affect the recovery and thus detection of extracellular acetylcholine in microdialysis studies.

Concepts and controversies in nonketotic hyperglycemia‐induced hemichorea: Further evidence from susceptibility‐weighted MR imaging

Hyperglycemia-induced hemichorea can show T1 hyperintensity of the contralateral striatum on MRI. This is thought to be due to petechial hemorrhages or gemistocytic astrocyte accumulation. This study explores the utility of susceptibility-weighted imaging (SWI) and diffusion-weighted imaging (DWI) in identifying the nature of these lesions. Three patients underwent MR imaging of the brain with SE T1, F SE T2, DWI, and SWI. T1 images showed hyperintensity predominantly involving the contralateral striatum, where mild (two cases) to moderate (one case) restricted diffusion (low apparent diffusion coefficient [ADC]) was detected on DWI. SWI demonstrated bilateral symmetrical hypointensities in the first two cases, suggesting age associated mineralization. In addition, increased susceptibility change (hypointensity) was also noted in the right putamen in the first and the third cases, suggesting paramagnetic mineral deposition. T1 hyperintensity may be from the protein hydration layer inside the cytoplasm of swollen gemistocytes appearing after an acute cerebral injury. These astrocytes also express metallothionein with zinc, which is thought to be the cause of asymmetric hypointensity of the posterior putamen on SWI. ADC values were thought to be useful for prognostication; however, they should be interpreted cautiously in the presence of susceptibility changes.

FDG PET Brain Imaging in Neuropsychiatric Systemic Lupus Erythematosis With Choreic Symptoms

Abstract: Chorea is a rare manifestation of neuropsychiatric systemic lupus erythematosus, and is probably caused by immune-mediated hypofunction of the contralateral striatum. Conventional imaging with brain computed tomography or magnetic resonance imaging often fails to show any structural lesions. We report a case of systemic lupus erythematosus-associated chorea in which brain F-18 flourodeoxyglucose positron emission tomography imaging showed disturbances in striatal metabolism in the absence of structural damage on magnetic resonance imaging. A follow-up positron emission tomography scan showed normalization of striatal metabolism, which was correlated with clinical remission.

Intracortical circuits of pyramidal neurons reflect their long-range axonal targets

Cortical columns generate separate streams of information that are distributed to numerous cortical and subcortical brain regions1. We asked whether local intracortical circuits reflect these different processing streams by testing if the intracortical connectivity among pyramids reflects their long-range axonal targets. We recorded simultaneously from up to four retrogradely labelled pyramids that projected to the superior colliculus, the contralateral striatum or the contralateral cortex to assess their synaptic connectivity. Here we show that the probability of synaptic connection depends on the functional identity of both the presynaptic and postsynaptic neurons. We first found that the frequency of monosynaptic connections among corticostriatal pyramids is significantly higher than among corticocortical or corticotectal pyramids. We then show that the probability of feedforward connections from corticocortical neurons to corticotectal pyramids is approximately three- to fourfold higher than the probability of monosynaptic connections among corticocortical or corticotectal cells. Moreover, we found that the average axodendritic overlap of the presynaptic and postsynaptic pyramids could not fully explain the differences in connection probability that we observed. The selective synaptic interactions we describe demonstrate that the organization of local networks of pyramidal cells reflects the long-range targets of both the presynaptic and postsynaptic neurons.

Time course changes of the striatum neuropil after unilateral dopamine depletion and the usefulness of the contralateral striatum as a control structure

Introduction: After unilateral dopamine depletion, some ipsilateral alterations occur and the contralateral structure has been utilized as control.Objective: Our aim is to analyse the evolution of the ultrastructural alterations of the ipsilateral and contralateral striata of the 6-hydroxydopamine lesioned rats to demonstrate that the contralateral striatum should not be used as control structure.Methods: After the surgery and the rotation behavior evaluation, animals were killed from 3 to 120 days after lesioning, and their striata were compared with those of aged rats.Results: The ultrastructural analysis shows increased diameter of the synaptic ending in ipsilateral (since the third day) and contralateral striata (since day 30) and an increase in perforated synaptic contacts.Conclusion: Our data suggest that the contralateral striatum should not be taken as control structure at least after 20–30 days after lesioning, as the alterations found here may result in wrong interpretations when comparing with the ipsilateral-lesioned one.

Differential astroglial activation in 6-hydroxydopamine models of Parkinson’s disease

In rat models of Parkinson’s disease, injections of 6-hydroxydopamine (6-OHDA) into different areas of the basal ganglia result in dopaminergic neurodegeneration in the substantia nigra. The extent and time course of the dopaminergic lesions varies between the models. While the effects on neurons have been extensively studied, little is known about the effects on astrocytes. We compared astrocytic activation (i.e. increase in number and staining intensity of glial fibrillary acidic protein immunoreactive cells) at the injection site and in downstream structures of the motor loop, i.e. the globus pallidus (GP) and the subthalamic nucleus (STN) following 6-OHDA lesion of the medial forebrain bundle (MFB) or the striatum. Lesions in both regions resulted in astrocytic activation at the lesion site, but their remote effects varied. MFB injections caused astrocytic activation in the ipsi- and contralateral striatum, whereas striatal injections resulted in astrocytic activation in the GP and STN. Since 6-OHDA injections into the MFB and the striatum result in complete and partial SNc lesions, respectively, we hypothesize that communication links exist between astrocytes, or between neurons and astrocytes, along neuronal pathways that transmit activating signals in response to neuronal damage—but only if the neuronal pathways are at least partially intact.

Mammalian cerebral metabolism and amino acid neurotransmission during hibernation

This report demonstrates that during the torpor phase of hibernation, hamsters utilize (14)C and (13)C glucose in torpor-specific brain metabolic pathways. Microdialysis of (14)C glucose into the striatum rapidly induced a steady state labeling of extracellular fluid (ECF) lactate and labeling of tissue GABA, glutamate, glutamine, and alanine in ipsilateral and contralateral striata. The same tissue metabolites were labeled in cortex, hypothalamus, and brainstem after microdialysis of (14)C lactate into the lateral ventricle. Serine, aspartate, glycine, taurine, tyrosine, and methionine were not synthesized from glucose or lactate during torpor. ECF levels of amino and organic acids were low and unchanging during torpor and increased late during arousal to cenothermia. Labeled intracellular (14)C GABA and glutamate were not communicated to the striatal ECF or ventricular space during torpor. (13)C NMR demonstrated rapid formation of lactate and functional tricarboxylic acid cycles in GABAergic and glutamatergic neurons, and enrichment of glutamine and alanine after i.v. (13)C glucose. Large changes in tissue levels of amino acids occur prior to or during entrance into torpor but not during torpor. It is proposed that cerebral intracellular dehydration, the enlargement of ECF and the biochemistries associated with brain water homeostasis may have a role in regulating hibernation.

Intratelencephalic corticostriatal neurons equally excite striatonigral and striatopallidal neurons and their discharge activity is selectively reduced in experimental parkinsonism

Striatonigral and striatopallidal neurons form distinct populations of striatal projection neurons. Their discharge activity is imbalanced after dopaminergic degeneration in Parkinson's disease. Striatal projection neurons receive massive cortical excitatory inputs from bilateral intratelencephalic (IT) neurons projecting to both the ipsilateral and contralateral striatum and from collateral axons of ipsilateral neurons that send their main axon through the pyramidal tract (PT). Previous anatomical studies in rats suggested that IT and PT inputs preferentially excite striatonigral and striatopallidal neurons, respectively. Here we used electrophysiological criteria to identify them with antidromic stimulations. We show that the spontaneous discharge activity of IT neurons is depressed, whereas that of PT neurons is not affected in the rat cortex ipsilateral to 6-hydroxydopamine injection. However, our functional experiments do not support the hypothesis of a differential cortical input to striatal pathways. Firstly, although the conduction velocity of PT neurons is 4.6 times faster than that of IT neurons, identified striatopallidal and striatonigral neurons exhibit identical latencies of their spike responses to electrical stimulation of the ipsilateral cortex. Secondly, although PT neurons are ipsilateral, both striatal populations exhibit similar sensitivity to the stimulation of the ipsilateral and contralateral cortex. We suggest that IT neurons provide the main excitatory input to both striatal populations and that the corticostriatal PT input is weaker. Therefore, our functional data do not support our previous hypothesis that the deficit of IT neurons associated with the dopaminergic depletion might contribute to the striatal imbalance. This imbalance might rather result from intrinsic striatal mechanisms.