Laboratory of the Cellular Physiology of Neurodegenerative Diseases
With life expectancy increasing, neurodegenerative diseases are taking an ever-increasing toll on society. Several of these diseases are characterized by a selective degeneration of particular classes of neurons. Our laboratory focuses on understanding how the physiology of vulnerable neurons contributes to their degeneration as well as studying adaptive physiological responses to degeneration within neural networks.
Our research focuses on Parkinson's disease and Huntington's disease. We study it using genetic and other models of the disorders. We also are interested in the cellular physiology of neurons and circuits in the Basal Ganglia. Our work combines neurophysiological experiments, advanced imaging techniqes and mathematical modeling.
We are currently seeking excellent and highly motivated graduate students/post-docs to join the lab.
Current and Future Projects
Alpha-synuclein and oxidative stress in neuron's at risk in Parkinson's disease
The formation of alpha-synuclein inclusions is the cardinal pathology of Parkinson’s disease. Their appearance is accompanied by free radical overproduction in affected neurons (such as dopamine cells). Decades of this oxidative stress presumably lead to cell death. However, we do not know whether alpha-synuclein causes oxidative stress per se. Inclusions appear in vagal motoneurons well before dopamine cells are implicated. We recently described how oxidative stress in vagal motoneurons is caused by an excessive influx of calcium ions. We hypothesize that alpha-synuclein causes oxidative stress by engaging this same mechanism. Using advance electrophysiological and brain imaging techniques, we will test whether treatment with calcium channel blockers -- widely used to treat hypertension -- can reduce the putative oxidative stress.
Network underlying the dopamine-acetylcholine balance
The dopamine-acetylcholine balance hypothesis has served for half a century as a widely- accepted clinical model of movement disorders of the basal ganglia (a brain region responsible for habitual behavior and motor plan selection). It states that a delicate balance between dopamine and acetylcholine levels is maintained in the striatum, the main input structure of the basal ganglia. Loss of this balance leads to a hypodopaminergic-hypercholinergic condition in striatum in Parkinson’s disease and to a hyperdopaminergic- hypocholinergic condition in Huntington’s disease. Despite strong evidence for this model, the underlying mechanism of the balance/imbalance is entirely unknown. Based on recent physiological studies, we are testing the hypothesis that the thalamic projection to acetylcholine release neurons in the striatum orchestrates the balance.
Acetylcholine releasing neurons in Huntington's disease
The main population of neurons in the striatum is severely decimated in Huntington’s disease. In contrast, the acetylcholine releasing neurons are relatively spared. Nevertheless, as mentioned above, there is a reduction in biochemical markers of acetylcholine in Huntington’s disease. We are currently studying adaptations in the input to these neurons and their intrinsic activity in models of Huntington's disease that might explain this paradox.
Goldberg JA, Boraud T, Maraton S, Haber SN, Vaadia E, and Bergman H. Enhanced synchrony among primary motor cortex neurons in the 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson's disease. Journal of Neuroscience, 22(11):4639-4653 (2002).
Goldberg JA, Kats SS, and Jaeger D. Globus pallidus discharge is coincident with striatal activity during global slow wave activity in the rat. Journal of Neuroscience, 23(31):10058-10063 (2003).
Goldberg JA, Rokni U, and Sompolinsky H. Patterns of ongoing activity and the functional architecture of the primary visual cortex. Neuron, 42(3):489- 500 (2004).
Goldberg JA, Rokni U, Boraud T, Vaadia E and Bergman H. Spike synchronization in the cortex-basal ganglia network of parkinsonian primates reflects global dynamics of the local field potentials. Journal of Neuroscience, 24(26):6003-6010 (2004).
Goldberg JA and Wilson CJ. Control of spontaneous firing patterns by the selective coupling of calcium currents to calcium activated potassium currents in striatal cholinergic interneurons. Journal of Neuroscience, 25(44):10230-10238 (2005).
Goldberg JA, Deister CA and Wilson CJ. Response properties and synchronization of rhythmically firing dendritic neurons. Journal of Neurophysiology, 97(1): 208-19 (2007).
Li S, Arbuthnott GW, Jutras M, Goldberg JA and Jaeger D. Resonant antidromic cortical circuit activation as a consequence of high-frequency subthalamic deep-brain stimulation. Journal of Neurophysiology 98(6):3525-3537 (2007).
Goldberg JA, Teagarden MA, Foehring RC and Wilson CJ. Non-equilibrium calcium dynamics regulate the autonomous firing pattern of rat striatal cholinergic interneurons. Journal of Neuroscience 29(26):8396-8407 (2009).
Ding JB, Guzman JN, Peterson JD, Goldberg JA and Surmeier DJ. Thalamic gating of corticostriatal signaling by cholinergic interneurons. Neuron 67:294-307 (2010).
Ahilea Anholt T, Ayal S and Goldberg JA. Recruitment and blocking properties of the CardioFit stimulation lead. Journal of Neural Engineering 8:034004 (2011).
Goldberg JA, Guzman JN, Estep C, Ilijic E, Kondapalli J, Sanchez-Padilla J and Surmeier DJ. Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson’s disease. Nature Neuroscience 15(10):1414-1421 (2012).
Goldberg JA, Atherton JF and Surmeier DJ. Spectral reconstruction of phase response curves reveals the synchronization properties of mouse globus pallidus neurons. Journal of Neurophysiology 110:2497-2506 (2013).
Cooper G, Lasser-Katz E, Simchovitz A, Sharon R, Soreq H, Surmeier DJ and Goldberg JA. Functional segregation of voltage-activated calcium channels in motoneurons of the dorsal motor nucleus of the vagus. Journal of Neurophysiology 114(3):1513-1520 (2015).
Tanimura A, Lim SA, Aceves Buendia JJ, Goldberg JA, Surmeier DJ. Cholinergic interneurons amplify corticostriatal synaptic responses in the Q175 model of Huntington's disease. Frontiers in Systems Neuroscience 10:102 (2016).
Lasser-Katz E, Simchovitz A, Chiu W-H, Oertel WH, Sharon R, Soreq H, Roeper J, Goldberg JA. Mutant alpha-Synuclein overexpression induces stressless pacemaking in vagal motoneurons at risk in Parkinson's disease. Journal of Neuroscience 37(1):47-57 (2017).
Aceves Buendia JJ, Tiroshi L, Chiu W-H, Goldberg JA. Selective remodelling of glutamatergic transmission to striatal cholinergic interneurons after dopamine depletion. European Journal of Neuroscience (in press).