Past events

Vibrissal information is relayed to the barrel cortex through at least two parallel pathways: a lemniscal pathway involving the ventroposterior medial thalamic nucleus (VPM), and a paralemniscal pathway involving the posteromedial nucleus (POm). I will review the role of the lemniscal system, focusing on the mechanisms by which VPM shapes the response properties of neurons in cortical barrels. I will argue that although analyses of these properties (e.g. receptive field structure and angular preference) have illuminated the process of input transformation in sensory pathways, they may have only limited ethological role. I will show that this lemniscal pathway is critical for temporal coding of somatosensory inputs. In the paralemniscal pathway, and in POm in particular, neurons respond poorly and unreliably to physiologically relevant stimuli. I will show that the GABAergic nucleus zona incerta (ZI) regulates POm activity is a state-dependent manner. This regulation is mediated by the cholinergic activating system, which enhances POm activity during states of arousal and vigilance. However, even in these states, POm neurons fail to reliably encode sensory inputs. I will show that POm is critically involved in coding noxious stimuli. Specifically, I will present evidence in support of the hypothesis that the phenomenon of central pain may be the result of suppressed inhibitory regulation of POm activity.

I will argue that living organisms can be characterized by their abilities to exchange information with their environment through sensing and acting. Moreover, the optimal interaction of an organism with its environment is determined by the information it can extract and store from the past about the future of its environment, on multiple time scales. Its optimal achievable performance is therefore bounded by the predictive-information of the environment, in some analogy with the entropy and channel-capacity bounds in Shannon's theory of communication. In that sense, life utilizes the predictability of its environment and act in order to increase its predictive capacity. This conceptual and quantitative framework can allow us to design and analyze experiments in neuroscience in a new way. I will discuss some recent applications to auditory and motor physiology.

Accumulating psychophysical and physiological evidence suggest the involvement of early visual areas in the process of visual integration and specifically in local facilitation of proximal and collinear stimuli. To investigate the early integration mechanisms at the population level, we performed voltage-sensitive dye imaging that is highly sensitive to subthreshold population activity, and imaged from the primary visual cortex (V1) and extrastriate cortex (V2) of a behaving monkey. The animal was trained on a simple fixation task while presented with collinear or non-collinear patterns of small gratings, Gabors or short oriented bars. Facilitation in terms of increased amplitude activity at the corresponding retinotopic site of the target was observed for low contrast targets presented as part of collinear or non-collinear pattern. The facilitation effect and its time course depended on the target flanker separation distance, suggesting the role of horizontal connections. Next, we compared the dynamics of cortical response. We found that the time course of responses increased faster in the collinear pattern as compared with the non-collinear pattern. Finally, to study synchronization, we calculated the spatial correlation of pixels at the target location and found that correlation was higher for the collinear pattern, suggesting that the neuronal code for collinear versus non-collinear pattern may be carried by synchronization and response dynamics rather than simply maximal amplitude of response. These results suggest that neuronal population activity in area V1 is involved in local visual integration processes, and specifically in the increased sensitivity for low-contrast visual stimuli surrounded by high contrast flankers. In the second part of my talk I will discuss repeating spatio-precise spatio-temporal patterns. Numerous studies of neuronal coding have reported precise time relations among spikes in cortical neurons. Here our main goal was to study whether information processing in the cortex involves precise spatio-temporal patterns and to detect and characterize those patterns among neuronal populations exploiting voltage-sensitive dye imaging (VSDI) in visual cortical areas of a fixating monkey. Our preliminary results demonstrate that spatio-temporal patterns do exist above chance level (p<0.0001). The spatial characteristics of those patterns are consistent with physiological studies regarding the interplay between different visual areas, and the temporal characteristics show that the majority of the patterns appear in a range of 10-20ms apart

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)

Abstract: Past neurobiological models of mood disorders have not considered etiology or a developmental perspective. Recently enough data regarding candidate genes and the impact of adverse early experience has been published that the beginnings of a plausible and heuristically useful hypothetical causal model can be proposed. This talk will integrate known effects of susceptibility genes and childhood adversity in explaining the psychopathology and biological phenotype of major depression including data from postmortem studies and in vivo brain imaging.

The last twenty years of intense research have provided convincing evidence for a role of regulation of gene expression in control of long-term neuronal plasticity, including learning and memory. Starting from our discovery&#8211;in late eighties&#8211;of c-fos activation in those phenomena, we have focused on correlating the expression of c-fos mRNA and c-Fos protein in various cognition-related brain structures with neuronal plasticity, learning and memory. The major conclusion from our studies, as well as those by the others, is that c-Fos and its functional form, AP-1 transcription factor, is the best correlate of learning processes, especially of a novelty of the behavioral information, whose processing constitutes the very foundation of the learning phenomenon. However, our understanding of exact biological function(s) of c-Fos/AP-1 still remains largely missing. Recently, an extracellular proteolytic system, composed of tissue inhibitor of matrix metalloproteinases, TIMP-1 and matrix metalloproteinase-9, MMP-9, has emerged as a major AP-1 target in hippocampal neurons responding to enhanced neuronal activity. Structural remodeling of the dendritic spines and synapses is essential for synaptic plasticity, underlying learning and memory. Matrix metalloproteinases are pivotal for tissue remodeling throughout the body, especially during development. Matrix metalloproteinase 9 (MMP-9) is an extracellularly operating enzyme that have recently been implicated in dendritic remodeling, synaptic plasticity, learning and memory (Szklarczyk et al., J. Neurosci., 2002; Nagy et al., J. Neurosci., 2006; Okulski et al., Biol. Psych., 2007). Furthermore, we have recently identified MMP-9 as a being produced, expressed and active at the synaptic contacts (Konopacki et al., Neuroscience, 2007; Michaluk et al., J. Biol. Chem., 2007; Wilczynski et al., J. Cell Biol. in press). Most recently, we have also found that MMP-9 plays a key pathogenic role in two animal models of temporal lobe epilepsy (TLE): kainate-evoked-epilepsy and pentylenetetrazole (PTZ) kindling-induced epilepsy. TLE is a devastating disease in which aberrant synaptic plasticity plays a major role Notably, we show that the sensitivity to PTZ-epileptogenesis is decreased in MMP-9 KO mice, but is increased in novel strain of transgenic rats, we have produced to overexpress MMP-9 selectively in neurons. Immunoelectron microscopy has revealed that MMP-9 associates with hippocampal dendritic spines bearing asymmetric (excitatory) synapses, where both the MMP-9 protein levels and enzymatic activity become strongly increased upon seizures. Further, we find that MMP-9-deficiency diminishes seizure-evoked pruning of dendritic spines and decreases aberrant synaptogenesis following mossy-fibers sprouting. The latter observation provides a possible mechanistic basis for the effect of MMP-9 on epileptogenesis. Our work suggests that a synaptic pool of MMP-9 is critical for the sequence of events that underlie the development of seizures in animal models of TLE.