Past events

Abstracting from physiological details, I will present a theory that suggests an explanation behind critical periods in learning as a natural consequence of learning dynamics under a small and realistic set of assumptions. Surprisingly, the same theory offers an explanation for other animal learning phenomena, such as the tendency to reverse to the status quo following a transient learning experience. Additionally, the theory suggests simple experiments that can be used to prove or refute it. If the time permits, as a commercial for future results, I will finish the talk with a brief overview of recent attempts at LANL for petascale simulations of the mammalian visual cortex.

Functional MRI (fMRI) studies have defined a series of visual processing regions in the human cortex, which are believed to enable visual recognition behaviors through a hierarchy of processing stages. At the higher stages in this hierarchy lie regions which preferentially respond to images of intact objects compared to other visual stimuli, a set of regions collectively termed object-selective cortex. Within object-selective cortex exist category-selective regions, which prefer particular categories of images over others (e.g., faces, body parts, houses or scenes). Initially these regions were considered non-retinotopic, but increasing evidence indicates substantial retinal position selectivity, and in some cases retinotopy, in these regions. What is the representation of the visual field in object-selective regions? Are separate object- and category-selective regions part of a single map or embedded within a set of distinct visual field maps? We scanned seven subjects on separate experiments to localize object/category-selective regions, and measure visual field maps (GE 3T scanner). For retinotopic experiments, subjects viewed moving bar stimuli containing different stimuli, including slowly drifting checkerboards and frontal face images. The bars extended out to around 14° eccentricity from the fovea, and had a width of ~2.6°. We employed a recently-developed method for estimating population receptive fields (pRFs) using fMRI (Dumoulin and Wandell, Neuroimage, 2008), which estimates pRF center and size for each cortical location. Face-containing bars produced substantially larger responses than checkerboards along the fusiform gyrus, improving our ability to measure visual field maps in these regions. Eccentricity maps revealed two foveal representations, which may correspond to visual field map clusters previously identified as VO and VT (Wandell et al., Neuro-opth. Jpn., 2006). These foveas are within or adjacent to fusiform face-selective regions, and separated by smoothly-varying extra-foveal maps which are less face-selective. For several subjects, pRF sizes systematically increased with eccentricity in face-selective regions. The distribution of pRF sizes were substantially larger than in earlier visual cortex, but comparable to recent measurements made in lateral occipital cortex. We find two spatially separate face-selective regions along the fusiform gyrus, with comparable visual field coverage, separated by a representation of intermediate eccentricities. This indicates these two regions are likely to fall within different visual field maps. Current work addresses possible effects of low-level visual features (e.g. spatial frequency) and stimulus visibility in driving the observed face-selective retinotopic responses. I will also present some preliminary data from retinotopic mapping with house-containing bars, and an examination of retinotopic organization in house- or scene-selective cortical regions.

Optogenetics, synthesizing microbial opsins and solid-state optics, has achieved the goal of millisecond-precision bidirectional control of defined cell types in freely behaving mammals, but has not yet been widely applied to neuroscience and neuropsychiatry experimental challenges. First, relevant to important basic science questions, we have now successfully developed methods to target and control several classes of modulatory neurons in behaving mammals and intact neural tissue, and we are probing and quantifying measures of altered circuit performance under optogenetic control of defined circuit elements to address longstanding questions about neural circuit dynamics. Second, relevant to neuropsychiatric disease questions, we have used this approach for depth targeting of hypothalamic cells (in this case, the hypocretin/orexin cells in the lateral hypothalamus), establishing for the first time a causal relationship between frequency-dependent activity of genetically defined neurons important in clinical neuropsychiatric disease and a complex orchestrated mammalian behavior. We also are now applying fast optical control and optical imaging to animal models of depression, Parkinson’s Disease, and altered social behavior relevant to autism. Insights into both normal circuit function and disease mechanisms are beginning to emerge from this multidisciplinary technological approach. Prof. Deisseroth is hosted by the students of the Department of Neurobiology, as a part of the departmental students-invited visiting scientist program.

Abstract: Using a rat model of drug relapse and craving, we previously found time-dependent increases in cocaine seeking induced by exposure to drug cues after withdrawal from the drug, suggesting that cocaine craving incubates over time. In this lecture, I will first summarize our earlier behavioral and neurophysiological studies on incubation of cocaine craving. I will then discuss in more detail results from more recent studies implicating neuronal activity in the ventromedial prefrontal cortex and glutamate synaptic plasticity in the nucleus accumbens in the incubation of cocaine craving. I will also briefly address the relevance of our rat findings to the understanding of relapse to drug use in humans. Selected references related to incubation of cocaine craving Grimm JW, Hope B, Wise RA, Shaham Y (2001) Incubation of cocaine craving after withdrawal. Nature 412:141-142 Grimm JW, Lu L, Hayashi T, Su TP, Hope BT, Shaham Y (2003) Time dependent increases in brain-derived neurotrophic factor (BDNF) protein levels within the mesolimbic dopamine system following withdrawal from cocaine: implications for incubation of cocaine craving. The Journal of Neuroscience 23:742-747 Lu L, Dempsey J, Liu S, Bossert J, Shaham Y (2004) A single infusion of BDNF into the ventral tegmental area induces long-lasting potentiation of cocaine-seeking after withdrawal. The Journal of Neuroscience 24:1604-1611 Lu L, Grimm JW, Hope BT, Shaham Y (2004) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47(S1): 214-227 (invited review for a special issue commemorating 30 years of NIDA research) Lu L, Hope BT, Dempsey J, Liu S, Bossert JM, Shaham Y (2005) Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nature Neuroscience 8:212-219 Shaham Y, Hope BT (2005) The role of neuroadaptations in relapse to drug seeking. Nature Neuroscience 8:1437-1439 (special issue on Neurobiology of Addiction) Lu L, Uejima JL, Gray SM, Bossert JM, Shaham Y (2007) Systemic and central amygdala injections of the mGluR2/3 agonist LY379268 attenuate the expression of incubation of cocaine craving. Biological Psychiatry 61:591-598 Koya E, Uejima J, Wihbey K, Bossert JM, Hope BT, Shaham Y (2008) Role of ventral medial prefrontal cortex in incubation of cocaine craving. Neuropharmacology (in press, for a special issue commemorating 35 years of NIDA research)) Conrad KL, Tseng K, Uejima J, Reimers J, Heng L, Shaham Y, Marinelli M, Wolf ME (2008) Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature (in press)

Although pain is a complex entity, understanding the mechanisms of pain will reveal clues for better control. Perception of nociceptive, inflammatory and neuropathic pain - although initiated by distinctive mechanisms - all depend to some degree on generation and transmission of noxious signals by specific sets of primary sensory afferent neurons, nociceptors. Local anesthetics, by blocking voltage-gated sodium channels, prevent the transmission of nociceptive information and therefore block pain. However, since all local anesthetics act non-selectively on all types of axons, they also cause a loss of innocuous sensation, motor paralysis and autonomic block. Thus, approaches that produce only a selective blockade of pain fibers are of great potential clinical importance. In my talk, I will present a novel method to selectively block pain sensation. Using capsaicin to activate the TRPV1 channel, the noxious thermo-sensitive transducer localized specifically to high-threshold nociceptors, we were able to introduce QX-314, a membrane impermeable and therefore clinically ineffective lidocaine derivative, into nociceptors, and thereby blocked their electrical activity. Neurons that did not express TRPV1 were not blocked by the combination of QX-314 and capsaicin. Injection of QX-314 and capsaicin in vivo together but not alone abolished the response to noxious mechanical and thermal stimuli, without any motor or tactile deficit. This approach could be used clinically to produce long lasting regional analgesia while preserving motor and autonomic function. In addition to applications for dental procedures, surgery and childbirth, this technique could also be used to diminish postoperative and cancer pain, as well as inflammatory and neuropathic pain. Moreover, using TRP channels as a “natural” drug delivery system will enable specific cationic drugs to be targeted only to those cells that express the TRP channel. This technique offers a new strategy for treating pain.

Fetal mesencephalic tissue has been used as a source of dopaminergic neurons for transplantation in clinical trials with Parkinson’s disease patients and in animal models of Parkinson’s disease. Due to the poor availability of human fetal tissue, and the ethical concerns associated with the use tissue from aborted fetuses, further development of the cell replacement therapy will critically depend on the access to alternative sources of cells for transplantation, based on the use of stem cells as a source of dopaminergic neurons. The recent discovery of Lmx1a and Msx1 as key determinant genes of mesencephalic dopaminergic neuron fate during development (Andersson et al. 2006) has opened new possibilities to drive undifferentiated stem cells towards fully functional mesencephalic dopaminergic neurons. Overexpression of these genes in stable embryonic stem (ES) cell lines is sufficient to generate neurons with almost 100% efficiency into a fully differentiated mesencephalic dopaminergic phenotype. The in vivo data obtained so far indicate that mesencephalic dopaminergic neurons can be generated in large numbers using this approach, and that they survive very well after transplantation to the striatum of 6-hydroxydopamine lesioned rats. In vivo, the Lmx1a- and Msx1-expressing cells develop into fully mature mesencephalic dopaminergic neurons, of both the A9 and A10 subtypes, and grow efficiently to form an extensive TH-positive axonal terminal network throughout the entire host striatum. Using this approach transplantable neurons with what appear to be a complete mesencephalic dopaminergic phenotype can be generated in large numbers from ES cell cultures.