Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala.

Overgeneralization of conditioned threat responses is a robust clinical marker of anxiety disorders. In overgeneralization, responses that are appropriate to threat-predicting cues are evoked by perceptually similar safety-predicting cues. Inappropriate learning of conditioned threat responses may thus form an etiological basis for anxiety disorders. The role of dopamine (DA) in memory encoding is well established. Indeed by signaling salience and valence, DA is thought to facilitate discriminative learning between stimuli representing safety or threat. However, the neuroanatomical and biochemical substrates through which DA modulates overgeneralization of threat responses remain poorly understood. Here we report that the modulation of DA D2 receptor (D2R) signaling bidirectionally regulates the consolidation of fear responses. While the blockade of D2R induces generalized threat responses, its stimulation facilitates discriminative learning between stimuli representing safety or threat. Moreover, we show that controlled threat generalization requires the coordinated activation of D2R in the bed nucleus of the stria terminalis and the central amygdala. Finally, we identify the mTORC1 cascade activation as an important molecular event by which D2R mediates its effects. These data reveal that D2R signaling in the extended amygdala constitutes an important checkpoint through which DA participates in the control of threat processing and the emergence of overgeneralized threat responses.

Axo-glial interactions regulate the localization of axonal paranodal proteins.

Mice incapable of synthesizing the abundant galactolipids of myelin exhibit disrupted paranodal axo-glial interactions in the central and peripheral nervous systems. Using these mutants, we have analyzed the role that axo-glial interactions play in the establishment of axonal protein distribution in the region of the node of Ranvier. Whereas the clustering of the nodal proteins, sodium channels, ankyrin(G), and neurofascin was only slightly affected, the distribution of potassium channels and paranodin, proteins that are normally concentrated in the regions juxtaposed to the node, was dramatically altered. The potassium channels, which are normally concentrated in the paranode/juxtaparanode, were not restricted to this region but were detected throughout the internode in the galactolipid-defi- cient mice. Paranodin/contactin-associated protein (Caspr), a paranodal protein that is a potential neuronal mediator of axon-myelin binding, was not concentrated in the paranodal regions but was diffusely distributed along the internodal regions. Collectively, these findings suggest that the myelin galactolipids are essential for the proper formation of axo-glial interactions and demonstrate that a disruption in these interactions results in profound abnormalities in the molecular organization of the paranodal axolemma.

The glycosylphosphatidyl inositol-anchored adhesion molecule F3/contactin is required for surface transport of paranodin/contactin-associated protein (caspr).

Paranodin/contactin-associated protein (caspr) is a transmembrane glycoprotein of the neurexin superfamily that is highly enriched in the paranodal regions of myelinated axons. We have investigated the role of its association with F3/contactin, a glycosylphosphatidyl inositol (GPI)-anchored neuronal adhesion molecule of the Ig superfamily. Paranodin was not expressed at the cell surface when transfected alone in CHO or neuroblastoma cells. Cotransfection with F3 resulted in plasma membrane delivery of paranodin, as analyzed by confocal microscopy and cell surface biotinylation. The region that mediates association with paranodin was mapped to the Ig domains of F3 by coimmunoprecipitation experiments. The association of paranodin with F3 allowed its recruitment to Triton X-100-insoluble microdomains. The GPI anchor of F3 was necessary, but not sufficient for surface expression of paranodin. F3-Ig, a form of F3 deleted of the fibronectin type III (FNIII) repeats, although GPI-linked and expressed at the cell surface, was not recovered in the microdomain fraction and was unable to promote cell surface targeting of paranodin. Thus, a cooperative effect between the GPI anchor, the FNIII repeats, and the Ig regions of F3 is required for recruitment of paranodin into lipid rafts and its sorting to the plasma membrane.

Regulation of a neuronal form of focal adhesion kinase by anandamide.

Anandamide is an endogenous ligand for central cannabinoid receptors and is released after neuronal depolarization. Anandamide increased protein tyrosine phosphorylation in rat hippocampal slices and neurons in culture. The action of anandamide resulted from the inhibition of adenylyl cyclase and cyclic adenosine 3', 5'-monophosphate-dependent protein kinase. One of the proteins phosphorylated in response to anandamide was an isoform of pp125-focal adhesion kinase (FAK+) expressed preferentially in neurons. Focal adhesion kinase is a tyrosine kinase involved in the interactions between the integrins and actin-based cytoskeleton. Thus, anandamide may exert neurotrophic effects and play a role in synaptic plasticity.

Paranodin, a glycoprotein of neuronal paranodal membranes.

Ranvier nodes are flanked by paranodal regions, at the level of which oligodendrocytes or Schwann cells interact closely with axons. Paranodes play a critical role in the physiological properties of myelinated nerve fibers. Paranodin, a prominent 180 kDa transmembrane neuronal glycoprotein, was purified and cloned from adult rat brain, and found to be highly concentrated in axonal membranes at their junction with myelinating glial cells, in paranodes of central and peripheral nerve fibers. The large extracellular domain of paranodin is related to neurexins, and its short intracellular tail binds protein 4.1, a cytoskeleton-anchoring protein. Paranodin may be a critical component of the macromolecular complex involved in the tight interactions between axons and myelinating glial cells characteristic of the paranodal region.

[Axon and Schwann cells... so far away, so close]. / Axones et cellules de Schwann... si loin, si proches.

Myelination was a major step in the evolution of the nervous system. Appearing first in jaw fish, myelination allows the fast and secure propagation of action potentials at a low energetic cost, and without exaggerated increase in axonal diameter. In the peripheral nervous system of mammals, myelination results from the tight interactions between Schwann cells and axons, leading to the formation of highly differentiated domains along the axon. The molecular determinants of these interactions are starting to be well identified. Their understanding provides a precise framework to interpret the defects, which occur in pathological circumstances. This review summarizes the present state of knowledge concerning axoglial interactions in peripheral nerves.

Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis.

Saltatory conduction in myelinated fibres depends on the specific molecular organization of highly specialized axonal domains at the node of Ranvier, the paranodal and the juxtaparanodal regions. Voltage-gated sodium channels (Na(v)) have been shown to be deployed along the naked demyelinated axon in experimental models of CNS demyelination and in multiple sclerosis lesions. Little is known about aggregation of nodal, paranodal and juxtaparanodal constituents during the repair process. We analysed by immunohistochemistry on free-floating sections from multiple sclerosis brains the expression and distribution of nodal (Na(v) channels), paranodal (paranodin/Caspr) and juxtaparanodal (K(v) channels and Caspr2) molecules in demyelinated and remyelinated lesions. Whereas in demyelinated lesions, paranodal and juxtaparanodal proteins are diffusely distributed on denuded axons, the distribution of Na(v) channels is heterogeneous, with a diffuse immunoreactivity but also few broad Na(v) channel aggregates in all demyelinated lesions. In contrast to the demyelinated plaques, all remyelinated lesions are characterized by the detection of aggregates of Na(v) channels, paranodin/Caspr, K(v) channels and Caspr2. Our data suggest that these aggregates precede remyelination, and that Na(v) channel aggregation is the initial event, followed by aggregation of paranodal and then juxtaparanodal axonal proteins. Remyelination takes place in multiple sclerosis tissue but myelin repair is often incomplete, and the reasons for this remyelination deficit are many. We suggest that a defect of Na(v) channel aggregation might be involved in the remyelination failure in demyelinated lesions with spared axons and oligodendroglial cells.

FAK and PYK2/CAKbeta in the nervous system: a link between neuronal activity, plasticity and survival?

A major aim of neurobiology today is to improve understanding of the signaling pathways that couple rapid events, such as the action potential and neurotransmitter release, to long-lasting changes in synaptic strength and increased neuronal survival. These adaptations involve interactions of neurons with other cells and with the extracellular matrix. They use, in part, the same molecular machinery that controls adhesion, motility or survival in non-neuronal cells. This machinery includes two homologous non-receptor tyrosine kinases, FAK and PYK2/CAKbeta, and the associated SRC-family tyrosine kinases. Specific brain isoforms of FAK with distinct properties are regulated by neurotransmitters, whereas PYK2/CAKbeta is highly sensitive to depolarization. The multiplicity of the pathways that can be activated by these tyrosine kinases indicates their importance in signal transduction in the adult brain.

[Role and regulation of dopamine D1 receptors in the striatum: implications for the genesis of dyskinesia in Parkinson's disease]. / Rôle et régulation du récepteur D1 de la dopamine dans le striatum: implications dans les dyskinésies de la maladie de Parkinson.

L-dopa treatment of Parkinson's disease is complicated in the long term by the appearance of dyskinesia. Hypersensitivity of D1 dopamine receptor has been suggested to play a role in these delayed adverse effects. Hypersensitivity of dopamine D1 receptor in Parkinson's disease can be accounted for by increased levels of Galphaolf, the stimulatory G protein which couples D1 receptor to adenylyl cyclase in the striatum. We here discuss the possible role of D1 receptor signal transduction in the genesis of L-dopa-induced dyskinesia in the light of Galphaolf regulation.

Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum.

In the striatum, dopamine D(1) and adenosine A(2A) receptors stimulate the production of cAMP, which is involved in neuromodulation and long-lasting changes in gene expression and synaptic function. Positive coupling of receptors to adenylyl cyclase can be mediated through the ubiquitous GTP-binding protein Galpha(S) subunit or through the olfactory isoform, Galpha(olf), which predominates in the striatum. In this study, using double in situ hybridization, we show that virtually all striatal efferent neurons, identified by the expression of preproenkephalin A, substance P, or D(1) receptor mRNA, contained high amounts of Galpha(olf) mRNA and undetectable levels of Galpha(s) mRNA. In contrast, the large cholinergic interneurons contained both Galpha(olf) and Galpha(s) transcripts. To assess the functional relationship between dopamine or adenosine receptors and G-proteins, we examined G-protein levels in the striatum of D(1) and A(2A) receptor knock-out mice. A selective increase in Galpha(olf) protein was observed in these animals, without change in mRNA levels. Conversely, Galpha(olf) levels were decreased in animals lacking a functional dopamine transporter. These results indicate that Galpha(olf) protein levels are regulated through D(1) and A(2A) receptor usage. To determine the functional consequences of changes in Galpha(olf) levels, we used heterozygous Galpha(olf) knock-out mice, which possess half of the normal Galpha(olf) levels. In these animals, the locomotor effects of amphetamine and caffeine, two psychostimulant drugs that affect dopamine and adenosine signaling, respectively, were markedly reduced. Together, these results identify Galpha(olf) as a critical and regulated component of both dopamine and adenosine signaling.

Bilateral cerebral metabolic alterations following lesion of the ventromedial thalamic nucleus: mapping by the 14C-deoxyglucose method in conscious rats.

The functional role of the ventromedial thalamic nucleus (VM) was investigated by means of the quantitative autoradiographic 14C-deoxyglucose method. Local cerebral glucose utilization (LCGU) was measured bilaterally in 53 discrete brain areas of conscious rats 1 week and 1 month following electrolytic lesion of the VM. There was no difference observed in the LCGU values between the two groups of lesioned animals. In the VM-lesioned rats glucose consumption was decreased in several ipsilateral (pre-frontal, frontal, cingulate, sensorimotor, visual) and in some contralateral (cingulate, sensorimotor, visual) cortical areas. Furthermore, LCGU values were depressed bilaterally in the striatum, hippocampus, dentate gyrus, substantia nigra compacta, superficial layers of the superior colliculus, oculomotor complex, and cerebellar dentate nuclei. Glucose utilization was diminished also in the deep layers of the superior colliculus and in the fastigial nucleus ipsilateral to the lesion. Within the thalamus, glucose metabolism was decreased in several nuclei either bilaterally (reticular, intralaminar, paralamellar mediodorsal) or ipsilaterally (lateroposterior, ventrobasal, ventrolateral, ventroanterior, and medioventral) to the lesion. A significant correlation between the percentage of injured VM and the regional metabolic depression was demonstrated in the areas displaying the most pronounced decrease in LCGU. These results support a widespread influence of the VM on brain function extending beyond the limits of purely motor systems and reveal the consequences of a unilateral lesion of the thalamus on metabolic activity in several contralateral structures.

Immunocytochemical localization of phosphatase inhibitor-1 in rat brain.

The localization of phosphatase inhibitor-1 was investigated in rat brain by use of immunocytochemistry. Studies were performed with an affinity purified IgG raised against purified rabbit skeletal muscle inhibitor-1. In rat brain tissue homogenates, this antibody reacted only with a 29 kDa protein corresponding to inhibitor-1. Immunocytochemical studies with this antibody revealed numerous immunoreactive cell bodies and fibers. The highest concentration of immunoreactive perikarya was observed in the caudate-putamen and nucleus accumbens, and these appeared to be exclusively medium-sized neurons. Other areas containing substantial populations of immunoreactive neurons included the suprachiasmatic nucleus of the hypothalamus, lateral hypothalamus, horizontal limb of the diagonal band of Broca, dentate gyrus of the hippocampal formation, habenula, superior colliculus, claustrum, endopiriform nuclei, and neocortex. The distribution of terminals containing inhibitor-1 coincided with the distribution of terminal fields known to originate from the above regions. Thus, plexuses of immunoreactive axons were seen in the globus pallidus, substantia nigra pars reticulata, paraventricular hypothalamus, dorsal thalamus, CA3 region of the hippocampus, and interpeduncular nucleus. These results demonstrate that phosphatase inhibitor-1, a cyclic AMP-regulated inhibitor of phosphatase-1, is differentially distributed in the rat CNS. Given the widespread role of protein phosphorylation and dephosphorylation in intracellular signal transduction, these results suggest that neurons containing high levels of inhibitor-1 may share common, hitherto unrecognized, properties in terms of neurotransmitter regulation and/or responsiveness.

ARPP-21, a cAMP-regulated phosphoprotein enriched in dopamine-innervated brain regions: tissue distribution and regulation of phosphorylation in rat brain.

ARPP-21 (cAMP-regulated phosphoprotein, Mr = 21,000 as determined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate), a phosphoprotein substrate for cAMP-dependent protein kinase, is unevenly distributed in adult rat brain. Using immunoblotting and phosphorylation in vitro followed by immunoprecipitation, ARPP-21 was found to be enriched in caudate-putamen, substantia nigra, nucleus accumbens and olfactory tubercle. Intermediate levels were found in cerebral cortex and hippocampus. ARPP-21 was very low in most other brain areas and was not detected in any of the peripheral tissues studied. Following unilateral lesion of the caudate-putamen with quinolinic acid, a marked decrease in the levels of ARPP-21 was observed in both the lesioned caudate-putamen (-75%) and the ipsilateral substantia nigra (-70%) compared with the unlesioned side. This result demonstrates the enrichment of ARPP-21 in striatonigral neurons. In slices of caudate-putamen, substantia nigra or cerebral cortex incubated in vitro, the phosphorylation of ARPP-21 was enhanced by 8-Br-cAMP, a stable analog of cAMP. In striatal slices, forskolin, a compound which stimulates adenylate cyclase directly, enhanced the phosphorylation of ARPP-21 with an EC50 of 0.5 microM. In conclusion, ARPP-21 is a neuron-specific phosphoprotein enriched in specific brain areas which are known to receive a rich dopaminergic innervation and to contain high levels of D1 dopamine receptors. The phosphorylation of ARPP-21 is likely to mediate some of the intracellular effects of neurotransmitters which stimulate adenylate cyclase in these regions, in particular dopamine and vasoactive intestinal peptide.

In vivo release of [3H]gamma-aminobutyric acid in the rat neostriatum--II. Opposing effects of D1 and D2 dopamine receptor stimulation in the dorsal caudate putamen.

The effects of several dopaminergic agonists and antagonists on the spontaneous release of [3H]gamma-aminobutyric acid were investigated in the dorsal striatum of halothane-anaesthetized rats. A push-pull cannula was implanted and the tissue was superfused continuously with a physiological medium containing [3H]glutamine, the precursor of [3H]GABA. Drugs were added to the superfusion medium. 2-Amino,6,7-dihydroxy,1,2,3,4-tetrahydro-naphtalene (ADTN, a mixed D1 and D2 receptor agonist) and D-amphetamine (a drug that enhances the release of endogenous dopamine) increased the release of 3H-GABA. The effect of ADTN was blocked by a D1 antagonist [R-(+),8-chloro, 7-hydroxy,2,3,4,5-tetrahydro,3-methyl,5-phenyl,1-H,3-benzazepine (SCH 23390)] but not by a D2 antagonist (S-sulpiride). Furthermore the stimulation of D1 receptors either by 2,3,4,5-tetrahydro,7,8-dihydroxy,1-phenyl,1-H,3-benzazepine or by D-amphetamine in the presence of S-sulpiride also enhanced the release of [3H]GABA. On the other hand, a selective D2 receptor agonist (3-(2-(N-3-hydroxy-phenylethyl)N-propylamino)ethyl-phenol) decreased the release of [3H]GABA. This effect was blocked in the presence of S-sulpiride. By itself the D1 receptor antagonist (SCH 23390) decreased the release of [3H]GABA whereas the D2 receptor antagonist (S-sulpiride) had no effect. It was concluded that stimulation of D1 and D2 receptors produces opposing effects on the spontaneous release of [3H]GABA in the dorsal striatum. Stimulation of D1 receptors facilitates the release of [3H]GABA whilst stimulation of D2 receptors inhibits it. The effect of D1 receptor stimulation appears to be predominant, and endogenous dopamine may activate tonically the release of GABA through these receptors in our experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of the bilateral corticostriatal glutamatergic projection by infusion of GABA into thalamic motor nuclei in the cat: an in vivo release study.

The unilateral application of GABA (10(-5) M; 30 min) into thalamic motor nuclei of the cat increases the release of dopamine in both caudate nuclei. This effect has been suggested to be related to an activation of the bilateral corticostriatal glutamatergic projection, glutamate exerting a presynaptic facilitatory influence on dopamine release. To explore this hypothesis further, halothane-anesthetized cats implanted with push-pull cannulae were used in order to examine the effects of such a GABA application on the release of glutamate in both caudate nuclei. Aspartate, alanine, glutamine, serine and tyrosine were also measured in the superfusates. The unilateral application of GABA (10(-5) M; 30 min) into thalamic motor nuclei increased the release of glutamate bilaterally. Although less pronounced, ipsi- or bilateral increases in the efflux of alanine, glutamine and tyrosine were also observed. Contralateral changes in the efflux of glutamate, alanine and tyrosine were prevented following acute section of the corpus callosum. In addition, when applied continuously into one caudate nucleus, 2-amino-5-phosphonovaleric acid, a blocker of N-methyl-D-aspartate receptors, prevented the GABA-induced increase in alanine or tyrosine efflux but did not affect the enhanced release of glutamate. These results confirm that the unilateral application of GABA in thalamic motor nuclei activates a thalamo-cortico-striatal neuronal loop leading to the stimulation of glutamate release in both caudate nuclei. Changes in the efflux of other amino acids could be linked to increased metabolic activity of striatal target cells resulting from the increased release of glutamate and from its effect on N-methyl-D-aspartate receptors.

In vivo release of [3H]gamma-aminobutyric acid in the rat neostriatum--I. Characterization and topographical heterogeneity of the effects of dopaminergic and cholinergic agents.

The release of [3H]gamma-aminobutyric acid continuously synthesized from [3H]glutamine was studied in the striatum of halothane-anaesthetized rats superfused with a push-pull cannula. The levels of spontaneously released [3H]GABA were identical in all striatal regions examined, but were found to be higher at the junction between the striatum and the globus pallidus. Superfusion with a medium enriched in K+ ions induced a concentration-dependent increase in [3H]GABA release. Superfusion with a Ca2+-free medium did not affect the spontaneous outflow of [3H]GABA but sharply reduced the release of [3H]GABA evoked by 30 mM K+. Locally applied tetrodotoxin (50 microM) decreased slightly the spontaneous release of [3H]GABA (-22%). When acetylcholine (50 or 500 microM) was added to a superfusion medium containing eserine (50 microM), the spontaneous release of [3H]GABA was enhanced in the ventral but not in the dorsal region of the striatum. The local application of 2,3,4,5-tetrahydro, 7,8,-dihydroxy, 1-phenyl, 1-H, 3-benzazepine (10 microM), a dopaminergic agonist acting preferentially on D1 receptors increased the release of [3H]GABA in the dorsal striatum (+32%) but decreased it slightly (-19%) in the ventral striatum. 3-(2-(N-3 hydroxyphenylethyl)N-propylamino)ethyl-phenol (50 microM), a preferential D2 receptor agonist, decreased [3H]GABA release when it was applied dorsally (-23%) but not ventrally in the striatum. It is concluded that the regulation of the release of [3H]GABA by acetylcholine and dopaminergic drugs is different in the dorsal and ventral regions of the striatum. These differences may be related to the existence of subpopulations of GABA neurons and may well have functional implications as suggested by behavioural studies.

Localization of cyclic GMP-dependent protein kinase in rat basal ganglia neurons.

Cyclic GMP-dependent protein kinase displays an uneven distribution in brain, being highly concentrated only in cerebellar Purkinje cells. Using DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32,000) as exogenous substrate, and performing assays in the absence or presence of the protein inhibitor of cyclic AMP-dependent protein kinase, we have now identified both cyclic AMP-dependent and cyclic GMP-dependent protein kinase activities in the rat neostriatum and substantia nigra. Quinolinic acid-induced degeneration of neostriatal neurons and the straitonigral fibers emanating from neostriatal neurons decreased the activities of both cyclic nucleotide-dependent enzymes by 70-85% in the neostriatum, while cyclic GMP-dependent protein kinase was decreased by 44% and cyclic AMP-dependent protein kinase was decreased by 18% in the substantia nigra. In the basal ganglia, cyclic GMP-dependent protein kinase therefore appears enriched in striatonigral neurons, while cyclic AMP-dependent protein kinase is present both in striatonigral neurons and in other cells. The results indicate that cyclic GMP-regulated protein phosphorylation may play a role in the function of distinct basal ganglion neurons.

Cloning of focal adhesion kinase, pp125FAK, from rat brain reveals multiple transcripts with different patterns of expression.

Focal adhesion kinase (pp125FAK, or FAK) is a cytoplasmic tyrosine kinase enriched in focal adhesions. We have screened a rat striatum cDNA library with a PCR-amplified cDNA probe specific for FAK messenger. Sequencing of multiple clones revealed the existence of three different 5'-leader sequences resulting from the combination of 5 conserved boxes. One of them contains a potential alternative initiation site, 78 base pairs upstream of that previously described. Another is 89% identical to a human genomic sequence located on chromosome 3. Most positive clones contained an insertion coding for three amino acids (Pro-Trp-Arg) in the region responsible for focal adhesion targeting. We propose to name this variant of the protein FAK +. The pattern of expression of the multiple forms of FAK was studied by RT-PCR and Southern hybridization with specific primers and probes. The different 5'-leader sequences were always found in the same proportions. In contrast, FAK + mRNA was found at very low levels in non-nervous tissues, whereas it was highly expressed in all brain regions. In cells in culture, it was present in astrocytes and enriched in neurons. These results demonstrate the existence of multiple forms of FAK transcript and protein, one of which, FAK +, may play a specific role in the nervous system.

Tyrosine phosphorylation of NMDA receptor in rat striatum: effects of 6-OH-dopamine lesions.

N-Methyl-D-aspartate (NMDA) glutamate receptor properties are subject to a fine tuning by several regulatory mechanisms including phosphorylation of the receptor subunits. Here we show that two of these subunits, NR2B and NR2A, are phosphorylated on tyrosine residues in vivo, in rat striatum, where NR2B is by far the most prominent tyrosine phosphorylated protein. Two weeks after unilateral lesioning of nigrostriatal dopaminergic neurones with 6-hydroxydopamine, tyrosine phosphorylation of NR2B was increased by approximately 20% in the ipsilateral striatum. The total amount of NR2B protein was unaltered. Thus, increased tyrosine phosphorylation of NR2B may account for some of the consequences of dopamine deprivation on corticostriatal transmission and may play a role in some forms of synaptic plasticity.

Adaptive reaction of nigral neurons following lesion of their ventromedial-thalamic projection field.

The response of reticulata-nigral neurons to injury of their ventromedial-thalamic (VM) projection was studied in the rat, by the autoradiographic [14C]deoxyglucose method. Electrolytic lesion of the VM induced reversible: reticulata hypoexcitability; and hyporesponsiveness of areas receiving reticulata efferents, to nigral electrical stimulus. The results suggest that distal axonal injury (in the VM) induces reversible rearrangement of functional properties in the nigral parent cells and their uninjured collaterals, as a retrograde reaction.