Showing papers by "Ann M. Graybiel published in 1999"

The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease.

Abstract: To achieve accuracy in studying the patterns of loss of midbrain dopamine-containing neurons in Parkinson's disease, we used compartmental patterns of calbindin D(28K) immunostaining to subdivide the substantia nigra with landmarks independent of the degenerative process. Within the substantia nigra pars compacta, we identified dopamine-containing neurons in the calbindin-rich regions ('matrix') and in five calbindin-poor pockets ('nigrosomes') defined by analysis of the three-dimensional networks formed by the calbindin-poor zones. These zones were recognizable in all of the brains, despite severe loss of dopamine-containing neurons. The degree of loss of dopamine-containing neurons in the substantia nigra pars compacta was related to the duration of the disease, and the cell loss followed a strict order. The degree of neuronal loss was significantly higher in the nigrosomes than in the matrix. Depletion was maximum (98%) in the main pocket (nigrosome 1), located in the caudal and mediolateral part of the substantia nigra pars compacta. Progressively less cell loss was detectable in more medial and more rostral nigrosomes, following the stereotyped order of nigrosome 1 > nigrosome 2 > nigrosome 4 > nigrosome 3 > nigrosome 5. A parallel, but lesser, caudorostral gradient of cell loss was observed for dopamine-containing neurons included in the matrix. This pattern of neuronal loss was consistent from one parkinsonian substantia nigra pars compacta to another. The spatiotemporal progression of neuronal loss related to disease duration can thus be drawn in the substantia nigra pars compacta for each Parkinson's disease patient: depletion begins in the main pocket (nigrosome 1) and then spreads to other nigrosomes and the matrix along rostral, medial and dorsal axes of progression.

Building neural representations of habits.

Abstract: Memories for habits and skills ("implicit or procedural memory") and memories for facts ("explicit or episodic memory") are built up in different brain systems and are vulnerable to different neurodegenerative disorders in humans. So that the striatum-based mechanisms underlying habit formation could be studied, chronic recordings from ensembles of striatal neurons were made with multiple tetrodes as rats learned a T-maze procedural task. Large and widely distributed changes in the neuronal activity patterns occurred in the sensorimotor striatum during behavioral acquisition, culminating in task-related activity emphasizing the beginning and end of the automatized procedure. The new ensemble patterns remained stable during weeks of subsequent performance of the same task. These results suggest that the encoding of action in the sensorimotor striatum undergoes dynamic reorganization as habit learning proceeds.

The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry.

Abstract: Parkinson's disease is characterized by massive degeneration of dopamine-containing neurons in the midbrain. However, the vulnerability of these neurons is heterogeneous both across different midbrain dopamine-containing cell groups and within the substantia nigra, the brain structure most affected in this disease. To determine the exact pattern of cell loss and to map the cellular distribution of candidate pathogenic molecules, it is necessary to have landmarks independent of the degenerative process by which to subdivide the substantia nigra. We have developed a protocol for this purpose based on immunostaining for calbindin D(28K), a protein present in striatonigral afferent fibres. We used it to examine post-mortem brain samples from seven subjects who had had no history of neurological or psychiatric disease. We found intense immunostaining for calbindin D(28K) associated with the neuropil of the ventral midbrain. Within the calbindin-positive region, there were conspicuous calbindin-poor zones. Analysed in serial sections, many of the calbindin-poor zones seen in individual sections were continuous with one another, forming elements of larger, branched three-dimensional structures. Sixty per cent of all dopamine-containing neurons in the substantia nigra pars compacta were located within the calbindin-rich zone, which we named the nigral matrix, and 40% were packed together within the calbindin-poor zones, which we named nigrosomes. We identified five different nigrosomes. This organization was consistent from one control brain to another. We propose that subdivision of the human substantia nigra based on patterns of calbindin immunostaining provides a key tool for analysing the organization of the substantia nigra and offers a new approach to analysing molecular expression patterns in the substantia nigra and the specific patterns of nigral cell degeneration in Parkinson's disease.

Nigrostriatal Dopamine System in Learning to Perform Sequential Motor Tasks in a Predictive Manner

Abstract: Neurons in the primate striatum and the substantia nigra pars compacta change their firing patterns during sensory-motor learning. To study the consequences of nigrostriatal dopamine depletion for ...

Cortically driven Fos induction in the striatum is amplified by local dopamine D2-class receptor blockade.

Abstract: Dopamine D2-class receptors have been shown to control the excitability of striatal neurons in response to cortical activation It has been unclear, however, whether such receptors could regulate the number of striatal neurons activated by cortical stimulation, and thus affect the population response of the striatum to its cortical inputs We used Fos induction as a readout to measure the ensemble response of striatal neurons to localized stimulation of the frontal cortex and tested for the effects of D2-class dopamine receptor blockade on this response In freely moving rats, we stimulated the frontal cortex by local epidural application of a dose of a GABAA receptor antagonist (picrotoxin) just threshold for inducing Fos in the striatum We combined this treatment with D2-class dopamine receptor antagonist treatments at dose levels also just threshold for inducing Fos, using either (i) systemic haloperidol or (ii) intrastriatal (-)sulpiride Both systemic and intrastriatal blockade of D2-class receptors sharply increased the numbers of striatal neurons exhibiting cortically evoked Fos induction These findings suggest that local activation of intrastriatal D2-class dopamine receptors can regulate the number of striatal neurons responsive to cortical inputs, thus dynamically shaping the flow of information through the striatum

Genes integrating signal transduction pathways

Abstract: The present invention describes the identification, isolation, sequencing and characterization of two human CalDAG-GEF, and two human cAMP-GEF genes, which are associated with the Ras pathway. Also identified are CalDAG-GEF gene homologues in mice and cAMP-GEF gene homologues in rats. Nucleic acids and proteins comprising or derived from the CalDAG-GEFs and/or cAMP-GEFs are useful in screening and diagnosing certain Ras-associated cancers, in identifying and developing therapeutics for treatment of certain Ras-associated cancers, and in producing cell lines and transgenic animals useful as models of Ras-associated cancers.