Parkinson Disease: Haber SN

Haber SN, Brucker JL. · Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA. · Front Biosci. · Pubmed #19273166 No free full text.

Abstract: Several lines of evidence indicate that the neural network that underlies the pathophysiology of obsessive-compulsive disorder and depression centers on the prefronto-basal ganglia system. Particularly involved are anterior cingulate cortex, the orbital prefrontal cortex, the ventral striatum, and parts of the thalamus. Additional integral parts of the network include, the amygdala, the midbrain dopamine cells and the serotonergic neurons. Collectively, these brain regions are involved in various aspects of reward-based learning and good decision-making skills. They are also associated with sadness and depression, pathological risk-taking, addictive behaviors, and obsessive-compulsive disorder. Two of the most successful deep brain stimulation targets for obsessive-compulsive disorder and depression are centered in white matter tracts. These targets were chosen for their central location and ability to capture specific ascending and descending connections, with a particular focus on fibers connecting the subgenual anterior cingulate and orbital cortex with the basal ganglia, thalamus, and amygdala. As more knowledge is obtained concerning the details of these connections, more precise targets may be possible.

Hurley SD, O'Banion MK, Song DD, Arana FS, Olschowka JA, Haber SN. · Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY 14642, USA. · Exp Neurol. · Pubmed #14769357 No free full text.

Abstract: Many investigators have reported extensive microglial activation in the mouse substantia nigra and striatum following acute, high-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. Our previous work demonstrated tyrosine hydroxylase (TH)-positive fiber sprouting in the striatum in monkeys that had received a partial dopaminergic lesion using a low-dose, chronic MPTP administration paradigm. To characterize the microglial response, we utilized HLA-DR (LN3) to immunolabel the class II major histocompatibility complex (MHC II). In MPTP-treated monkeys, there was an intense microglial response in the substantia nigra, nigrostriatal tract, and in both segments of the globus pallidus. This response was morphologically heterogeneous, with commingled ramified, activated, and multicellular morphologies throughout the extent of these basal ganglia structures. Surprisingly, there was little evidence of microglial reactivity in the striatum despite evidence of neurodegeneration-by silver labeling and by loss of TH immunolabeling. Moreover, this pattern of microglial reactivity was the same in all animals that had received MPTP and seemed to be independent of the degree of neurotoxin-induced neurodegeneration. Thus, we conclude that microglial reactivity, per se, is not consistently associated with neurodegeneration, but depends on regional differences.

Goldberg JA, Boraud T, Maraton S, Haber SN, Vaadia E, Bergman H. · Department of Physiology, The Hebrew University-Hadassah Medical School, the Interdisciplinary Center for Neural Computation, The Hebrew University, Jerusalem 91120, Israel. · J Neurosci. · Pubmed #12040070 links to  free full text

Abstract: Primary motor cortex (MI) neurons discharge vigorously during voluntary movement. A cardinal symptom of Parkinson's disease (PD) is poverty of movement (akinesia). Current models of PD thus hypothesize that increased inhibitory pallidal output reduces firing rates in frontal cortex, including MI, resulting in akinesia and muscle rigidity. We recorded the simultaneous spontaneous discharge of several neurons in the arm-related area of MI of two monkeys and in the globus pallidus (GP) of one of the two. Accelerometers were fastened to the forelimbs to detect movement, and surface electromyograms were recorded from the contralateral arm of one monkey. The recordings were conducted before and after systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rendering the animals severely akinetic and rigid with little or no tremor. The mean spontaneous MI rates during periods of immobility (four to five spikes/sec) did not change after MPTP; however, in this parkinsonian state, MI neurons discharged in long bursts (sometimes >2 sec long). These bursts were synchronized across many cells but failed to elicit detectable movement, indicating that even robust synchronous MI discharge need not result in movement. These synchronized population bursts were absent from the GP and were on a larger timescale than oscillatory synchrony found in the GP of tremulous MPTP primates, suggesting that MI parkinsonian synchrony arises independently of basal ganglia dynamics. After MPTP, MI neurons responded more vigorously and with less specificity to passive limb movement. Abnormal MI firing patterns and synchronization, rather than reduced firing rates, may underlie PD akinesia and persistent muscle rigidity.