D. James "Jim" Surmeier (born December 7, 1951), an American neuroscientist and physiologist of note, is the Nathan Smith Davis Professor and Chair in the Department of Neuroscience at Northwestern University Feinberg School of Medicine. His research is focused on the cellular physiology and circuit properties of the basal ganglia in health and disease, primarily Parkinson's and Huntington's disease as well as pain. [1]
Surmeier graduated summa cum laude from University of Idaho in 1975, with a double major in mathematics and psychology. He then received a master's degree in mathematics from the University of Oregon (1976) and a PhD in Physiology-Psychology from University of Washington (1983), where he worked in the lab of Arnold Towe. For his postdoctoral training, he worked with first, William Willis (1983-1985) and then Stephen Kitai (1986-1989). He then accepted a faculty position in the University of Tennessee, where he received tenure before moving to Northwestern University Feinberg School of Medicine in 1998. He was subsequently named the chair of Department of Physiology at the Northwestern University Feinberg School of Medicine in 2001. [2] [3]
Aa a graduate student, Surmeier characterized the physiological and anatomic heterogeneity in the slowly adapting proprioceptive neurons in the cat cuneate nucleus before going on to study the primate spinothalamic neurons and the effect of noxious thermal stimulation on their physiology. It was in Kitai's lab that he first became interested in the basal ganglia and started investigating the effects of dopamine in the brain, a fundamental question that has driven a lot of his subsequent research as an independent scientist.
By mid-90s, despite widespread consensus regarding the clinical relevance of striatal dopaminergic signaling, the distribution and segregation of different classes of dopamine receptors, into either the same or distinct neuronal populations was unclear and remained widely debated. In pioneering experiments, using patch clamp recordings in conjunction with single cell gene profiling through RT-PCR, Surmeier reconciled the seemingly confounding results from anatomical and functional studies by showing that the direct (striatonigral) and indirect pathway (striatopallidal) striatal projection neurons predominantly expressed either the D1 or D2 dopamine receptors. [4] Following this discovery, using pharmacology and spike-timing-dependent plasticity (STDP) protocols in genetically identified D1 or D2 receptor expressing neurons, Surmeier elucidated the distinct roles played by both the receptors in the induction of long-term potentiation and depression at the cortico-striatal synapses. [5] Simultaneously, he also showed that in projection neurons that do not express the D2 receptors, synaptic depression dependent on D2 receptor activation is mediated by D2 receptors in cholinergic neurons, M1 muscarinic receptor activation resulting in reduced calcium channel, CaV1.3 opening in projection neurons and endocannabinoid signaling. [6] [7] Understanding the opposing effects of D1 and D2 receptor signaling and the consequent insights into the dopaminergic modulation of bi-directional synaptic plasticity in the direct and indirect spiny neurons was a conceptual advance that has proven fundamental to understanding striatal function in both behavioral adaptation as well as Parkinson's disease pathology, and continues to provide a foundation for current models of how dopamine controls striatal circuitry. [8]
Around the same time, using multi-disciplinary approaches, his lab provided a possible explanation for the striatopallidal pathway dysfunction associated with Parkinson's disease and dopamine depletion by demonstrating a calcium channel (CaV1.3) dependent loss of excitatory synapses in the indirect pathway spiny neurons in a rodent model of the disease. [9] Loss of striatal dopamine results in decreased M4 (muscarinic acetylcholine auto receptor) signaling along with an up-regulation of RGS4 (regulators of G protein signaling) expression in cholinergic neurons, culminating in increased cholinergic tone. [10] Following dopamine depletion leading to increase in striatal acetylcholine levels, M1 muscarinic receptor activation in the indirect pathway spiny neurons results in down-regulation of dendritic potassium channels, Kir2, elevating the dendritic excitability and consequently the impact of synaptically released glutamate in these neurons. [11] Surmeier's work characterizing the corticostriatal and thalamostriatal synapses as well as the firing pattern of striatal cholinergic interneurons provides a potential mechanism for an important behavioral neuroscience problem of how salient external stimuli suppress ongoing behavior and direct attention. [12] [13] The dopamine modulated cholinergic burst-pause firing pattern depends on thalamic activation and results in M2 (muscarinic acetylcholine) receptor mediated presynaptic inhibition of glutamatergic transmission and M1 (muscarinic acetylcholine) receptor mediated enhanced D2 neuronal excitability. As a result, the response of the "no-go" pathway (D2 receptor expressing striatopallidal neurons) to depolarizing cortical input is enhanced, providing a potential neural substrate for attentional shift. Collectively, work from Surmeier's lab suggests that not only dopamine but acetylcholine also has differential effects on striatal projection neurons furthering the idea that striatal dopamine/acetylcholine balance is a potential target for therapeutic intervention in diseases marked by striatal dysfunction and sheds light on how striatal neurons and circuits both change and adapt in response to disease states. [11] [14]
Surmeier's work to functionally dissect the direct and indirect pathway striatal projection neurons and characterizing their response to dopamine not only confirmed the transcriptomal dichotomy between these two classes of projection neuron but also defined for the first time how dopamine and acetylcholine differentially modulated their intrinsic excitability through G-protein coupled receptors. [15] [13] In his later career, Surmeier has pioneered the application of two-photon laser scanning microcopy to brain slice recordings to study dendritic physiology and synaptic plasticity of striatal neurons in Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease and chronic pain. [9] [5] [16] [17] [18] These studies have revealed how dopamine controls striatal synaptic plasticity, complementing earlier work focusing on short-term intrinsic excitability. Of note is the discovery that striatal projection neurons manifest forms of homeostatic plasticity that serve to normalize basal ganglia function despite ongoing disease pathology, particularly in Parkinson's disease. [19]
Another major contribution of Surmeier is the characterization of the electrophysiological phenotypes of neurons at-risk in Parkinson's disease. Using a combination of patch clamp electrophysiology and two photon laser scanning microscopy to monitor key intracellular variables like Ca2+ concentration, mitochondrial redox status and cytosolic ATP levels, these studies have found that a wide array of neurons at-risk in Parkinson's disease – substantia nigra dopaminergic neurons, locus ceruleus adrenergic neurons, dorsal motor nucleus of the vagus cholinergic neurons and pedunculopontine cholinergic neurons – have a similar and distinctive physiological phenotype that creates basal oxidant stress in mitochondria. [20] [21] [22] [23] Oxidant stress has long been hypothesized to be a driver of pathogenesis in Parkinson's disease but it was not recognized that oxidant stress was a feature of healthy, at-risk neurons, reflecting an ancient a feed-forward control mechanism of mitochondrial respiration driven by plasma membrane Ca2+ channels with a Cav1 pore-forming subunit.
This connection between physiological phenotype and Parkinson's disease was subsequently confirmed by epidemiological studies showing that human use of negative allosteric modulators of Cav1 channels (dihydropyridines) was associated with a significant reduction in risk of developing Parkinson's disease. [24] [25] [26] [27] [28] These combined observations motivated Phase 2 and now Phase 3 clinical trials with the dihydropyridine isradipine; this 5-year trial will be completed in late 2018. [29] [30] If successful, isradipine would be the first disease modifying therapy for Parkinson's disease.
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.
The striatum or corpus striatum is a nucleus in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamatergic and dopaminergic inputs from different sources; and serves as the primary input to the rest of the basal ganglia.
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.
Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle.
The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.
Dopaminergic pathways in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.
The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum in the forebrain. It is one of the four major dopamine pathways in the brain, and is critical in the production of movement as part of a system called the basal ganglia motor loop. Dopaminergic neurons of this pathway release dopamine from axon terminals that synapse onto GABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), located in the striatum.
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second messenger signaling cascade that induces a broad, long-lasting signal. This modulation can last for hundreds of milliseconds to several minutes. Some of the effects of neuromodulators include: altering intrinsic firing activity, increasing or decreasing voltage-dependent currents, altering synaptic efficacy, increasing bursting activity and reconfigurating synaptic connectivity.
The basal ganglia form a major brain system in all species of vertebrates, but in primates there are special features that justify a separate consideration. As in other vertebrates, the primate basal ganglia can be divided into striatal, pallidal, nigral, and subthalamic components. In primates, however, there are two pallidal subdivisions called the external globus pallidus (GPe) and internal globus pallidus (GPi). Also in primates, the dorsal striatum is divided by a large tract called the internal capsule into two masses named the caudate nucleus and the putamen—in most other species no such division exists, and only the striatum as a whole is recognized. Beyond this, there is a complex circuitry of connections between the striatum and cortex that is specific to primates. This complexity reflects the difference in functioning of different cortical areas in the primate brain.
Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of GABAergic inhibitory cell representing 95% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary phenotypes : D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway. Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.
The muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein that, in humans, is encoded by the CHRM4 gene.
Cholinergic receptor, nicotinic, alpha 6, also known as nAChRα6, is a protein that in humans is encoded by the CHRNA6 gene. The CHRNA6 gene codes for the α6 nicotinic receptor subunit that is found in certain types of nicotinic acetylcholine receptors found primarily in the brain. Neural nicotinic acetylcholine receptors containing α6 subunits are expressed on dopamine-releasing neurons in the midbrain, and dopamine release following activation of these neurons is thought to be involved in the addictive properties of nicotine. Due to their selective localisation on dopaminergic neurons, α6-containing nACh receptors have also been suggested as a possible therapeutic target for the treatment of Parkinson's disease. In addition to nicotine, research in animals has implicated alpha-6-containing nAChRs in the abusive and addictive properties of ethanol, with mecamylamine demonstrating a potent ability to block these properties.
Xanomeline is a small molecule muscarinic acetylcholine receptor agonist that was first synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the treatment of central nervous system disorders.
John P. Walsh is an American academic who is an associate professor at the USC Davis School of Gerontology as well as a member of USC's Neuroscience Program. His main research interest is the physiology of basal ganglia-related brain disease.
The cortico-basal ganglia-thalamo-cortical loop is a system of neural circuits in the brain. The loop involves connections between the cortex, the basal ganglia, the thalamus, and back to the cortex. It is of particular relevance to hyperkinetic and hypokinetic movement disorders, such as Parkinson's disease and Huntington's disease, as well as to mental disorders of control, such as attention deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), and Tourette syndrome.
Stephanie J. Cragg is a full Professor of Neuroscience at the University of Oxford. She holds a joint appointment as Professor in the University Department of Physiology, Anatomy and Genetics and as Tutor for Medicine, Fellow and Director of Studies at the college Christ Church, Oxford.