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2014
Tal, N, Yonatan L.  2014.  Spatial Generalization in Operant Learning: Lessons from Professional Basketball. PLoS Computational Biology . 10(5):e1003623. Abstract
In operant learning, behaviors are reinforced or inhibited in response to the consequences of similar actions taken in the past. However, because in natural environments the “same” situation never recurs, it is essential for the learner to decide what “similar” is so that he can generalize from experience in one state of the world to future actions in different states of the world. The computational principles underlying this generalization are poorly understood, in particular because natural environments are typically too complex to study quantitatively. In this paper we study the principles underlying generalization in operant learning of professional basketball players. In particular, we utilize detailed information about the spatial organization of shot locations to study how players adapt their attacking strategy in real time according to recent events in the game. To quantify this learning, we study how a make \ miss from one location in the court affects the probabilities of shooting from different locations. We show that generalization is not a spatially-local process, nor is governed by the difficulty of the shot. Rather, to a first approximation, players use a simplified binary representation of the court into 2 pt and 3 pt zones. This result indicates that rather than using low-level features, generalization is determined by high-level cognitive processes that incorporate the abstract rules of the game.
Gianluigi, M, Hanan S, Yonatan L.  2014.  The Misbehavior of Reinforcement Learning. Proceedings of the IEEE. 102(4):528-541. Abstract pdf FURTHER THOUGHTS
Organisms modify their behavior in response to its consequences, a phenomenon referred to as operant learning. The computational principles and neural mechanisms underlying operant learning are a subject of extensive experimental and theoretical investigations. Theoretical approaches largely rely on concepts and algorithms from reinforcement learning. The dominant view is that organisms maintain a value function, that is, a set of estimates of the cumulative future rewards associated with the different behavioral options. These values are then used to select actions. Learning in this framework results from the update of these values depending on experience of the consequences of past actions. An alternative view questions the applicability of such a computational scheme to many real-life situations. Instead, it posits that organisms exploit the intrinsic variability in their action–selection mechanism(s) to modify their behavior, e.g., via stochastic gradient ascent, without the need of an explicit representation of values. In this review, we compare these two approaches in terms of their computational power and flexibility, their putative neural correlates, and, finally, in terms of their ability to account for behavior as observed in repeated-choice experiments. We discuss the successes and failures of these alternative approaches in explaining the observed patterns of choice behavior. We conclude by identifying some of the important challenges to a comprehensive theory of operant learning.
Shteingart, H, Loewenstein Y.  2014.  Reinforcement learning and human behavior. Current Opinion in Neurobiology. 25:93-98. AbstractPDF
The dominant computational approach to model operant learning and its underlying neural activity is model-free reinforcement learning (RL). However, there is accumulating behavioral and neuronal-related evidence that human (and animal) operant learning is far more multifaceted. Theoretical advances in RL, such as hierarchical and model-based RL extend the explanatory power of RL to account for some of these findings. Nevertheless, some other aspects of human behavior remain inexplicable even in the simplest tasks. Here we review developments and remaining challenges in relating RL models to human operant learning. In particular, we emphasize that learning a model of the world is an essential step before or in parallel to learning the policy in RL and discuss alternative models that directly learn a policy without an explicit world model in terms of state-action pairs.
Grodzinsky, Y, Nelken I.  2014.  The Neural Code That Makes Us Human. Science. 343(978):978-979.science-2014-grodzinsky-978-9.pdf
Pehlevan, C, Sompolinsky H.  2014.  Selectivity and Sparseness in Randomly Connected Balanced Networks. PLOS ONE. 9(2) Abstract
Neurons in sensory cortex show stimulus selectivity and sparse population response, even in cases where no strong functionally specific structure in connectivity can be detected. This raises the question whether selectivity and sparseness can be generated and maintained in randomly connected networks. We consider a recurrent network of excitatory and inhibitory spiking neurons with random connectivity, driven by random projections from an input layer of stimulus selective neurons. In this architecture, the stimulus-to-stimulus and neuron-to-neuron modulation of total synaptic input is weak compared to the mean input. Surprisingly, we show that in the balanced state the network can still support high stimulus selectivity and sparse population response. In the balanced state, strong synapses amplify the variation in synaptic input and recurrent inhibition cancels the mean. Functional specificity in connectivity emerges due to the inhomogeneity caused by the generative statistical rule used to build the network. We further elucidate the mechanism behind and evaluate the effects of model parameters on population sparseness and stimulus selectivity. Network response to mixtures of stimuli is investigated. It is shown that a balanced state with unselective inhibition can be achieved with densely connected input to inhibitory population. Balanced networks exhibit the ‘‘paradoxical’’ effect: an increase in excitatory drive to inhibition leads to decreased inhibitory population firing rate. We compare and contrast selectivity and sparseness generated by the balanced network to randomly connected unbalanced networks. Finally, we discuss our results in light of experiments.
Gjorgjieva, J, Sompolinsky H, Markus M.  2014.  Benefits of pathway splitting in sensory coding. The Journal of Neuroscience. 0270-6474/14/3412127-18$15.00/0 Abstract
In many sensory systems, the neural signal splits into multiple parallel pathways. For example, in the mammalian retina, ∼20 types of retinal ganglion cells transmit information about the visual scene to the brain. The purpose of this profuse and early pathway splitting remains unknown. We examine a common instance of splitting into ON and OFF neurons excited by increments and decrements of light intensity in the visual scene, respectively. We test the hypothesis that pathway splitting enables more efficient encoding of sensory stimuli. Specifically, we compare a model system with an ON and an OFF neuron to one with two ON neurons. Surprisingly, the optimal ON-OFF system transmits the same information as the optimal ON-ON system, if one constrains the maximal firing rate of the neurons. However, the ON-OFF system uses fewer spikes on average to transmit this information. This superiority of the ON-OFF system is also observed when the two systems are optimized while constraining their mean firing rate. The efficiency gain for the ON-OFF split is comparable with that derived from decorrelation, a well known processing strategy of early sensory systems. The gain can be orders of magnitude larger when the ecologically important stimuli are rare but large events of either polarity. The ON-OFF system also provides a better code for extracting information by a linear downstream decoder. The results suggest that the evolution of ON-OFF diversification in sensory systems may be driven by the benefits of lowering average metabolic cost, especially in a world in which the relevant stimuli are sparse.
Burak, Y.  2014.  Spatial coding and attractor dynamics of grid cells in the entorhinal cortex. Current Opinion in Neurobiology. 25:169-175.burak_2014.pdf
Ben, E, Eilon V.  2014.  Spatial computation with gamma oscillations. Front Syst. Neuros. 8(165)
Roth, ZN, Zohary E.  2014.  Fingerprints of Learned Object Recognition Seen in the fMRI Activation Patterns of Lateral Occipital Complex. Cerebral Cortex. :bhu042.
Adam, Y, Livneh Y, Miyamichi K, Groysman M, Luo L, Mizrahi A.  2014.  Functional transformations of odor inputs in the mouse olfactory bulb. Frontiers in Neural Circuits. 8 Abstract
Sensory inputs from the nasal epithelium to the olfactory bulb (OB) are organized as a discrete map in the glomerular layer (GL). This map is then modulated by distinct types of local neurons and transmitted to higher brain areas via mitral and tufted cells. Little is known about the functional organization of the circuits downstream of glomeruli. We used in vivo two-photon calcium imaging for large scale functional mapping of distinct neuronal populations in the mouse OB, at single cell resolution. Specifically, we imaged odor responses of mitral cells (MCs), tufted cells (TCs) and glomerular interneurons (GL-INs). Mitral cells population activity was heterogeneous and only mildly correlated with the olfactory receptor neuron (ORN) inputs, supporting the view that discrete input maps undergo significant transformations at the output level of the OB. In contrast, population activity profiles of TCs were dense, and highly correlated with the odor inputs in both space and time. Glomerular interneurons were also highly correlated with the ORN inputs, but showed higher activation thresholds suggesting that these neurons are driven by strongly activated glomeruli. Temporally, upon persistent odor exposure, TCs quickly adapted. In contrast, both MCs and GL-INs showed diverse temporal response patterns, suggesting that GL-INs could contribute to the transformations MCs undergo at slow time scales. Our data suggest that sensory odor maps are transformed by TCs and MCs in different ways forming two distinct and parallel information streams.
Porat, Y, Orlov T, McKyton A, Zohary E.  2014.  Sensitivity to spatiotopic location in the human visual system. Journal of Vision. 14:1230–1230.
Moreh, E, Malkinson T S, Zohary E, Soroker N.  2014.  Visual Memory in Unilateral Spatial Neglect: Immediate Recall versus Delayed Recognition.
2013
Avital, A, Shiran K, Inna F, Yifat P, Hagai B.  2013.  Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons.. Front Syst. Neurosci.. 7(47) Abstract
The striatum is populated by a single projection neuron group, the medium spiny neurons (MSNs), and several groups of interneurons. Two of the electrophysiologically well-characterized striatal interneuron groups are the tonically active neurons (TANs), which are presumably cholinergic interneurons, and the fast spiking interneurons (FSIs), presumably parvalbumin (PV) expressing GABAergic interneurons. To better understand striatal processing it is thus crucial to define the functional relationship between MSNs and these interneurons in the awake and behaving animal. We used multiple electrodes and standard physiological methods to simultaneously record MSN spiking activity and the activity of TANs or FSIs from monkeys engaged in a classical conditioning paradigm. All three cell populations were highly responsive to the behavioral task. However, they displayed different average response profiles and a different degree of response synchronization (signal correlation). TANs displayed the most transient and synchronized response, MSNs the most diverse and sustained response and FSIs were in between on both parameters. We did not find evidence for direct monosynaptic connectivity between the MSNs and either the TANs or the FSIs. However, while the cross correlation histograms of TAN to MSN pairs were flat, those of FSI to MSN displayed positive asymmetrical broad peaks. The FSI-MSN correlogram profile implies that the spikes of MSNs follow those of FSIs and both are driven by a common, most likely cortical, input. Thus, the two populations of striatal interneurons are probably driven by different afferents and play complementary functional roles in the physiology of the striatal microcircuit.
Renana, E, Reuben S, Eduard L, Ovadya R, Shay M, Tamir B-H, Hagai B, Zvi I.  2013.  Asymmetric right/left encodind of emotions in the human subthalamic nucleus. Front Syst. Neurosci.. 7(69) Abstract
Emotional processing is lateralized to the non-dominant brain hemisphere. However, there is no clear spatial model for lateralization of emotional domains in the basal ganglia. The subthalamic nucleus (STN), an input structure in the basal ganglia network, plays a major role in the pathophysiology of Parkinson's disease (PD). This role is probably not limited only to the motor deficits of PD, but may also span the emotional and cognitive deficits commonly observed in PD patients. Beta oscillations (12-30 Hz), the electrophysiological signature of PD, are restricted to the dorsolateral part of the STN that corresponds to the anatomically defined sensorimotor STN. The more medial, more anterior and more ventral parts of the STN are thought to correspond to the anatomically defined limbic and associative territories of the STN. Surprisingly, little is known about the electrophysiological properties of the non-motor domains of the STN, nor about electrophysiological differences between right and left STNs. In this study, microelectrodes were utilized to record the STN spontaneous spiking activity and responses to vocal non-verbal emotional stimuli during deep brain stimulation (DBS) surgeries in human PD patients. The oscillation properties of the STN neurons were used to map the dorsal oscillatory and the ventral non-oscillatory regions of the STN. Emotive auditory stimulation evoked activity in the ventral non-oscillatory region of the right STN. These responses were not observed in the left ventral STN or in the dorsal regions of either the right or left STN. Therefore, our results suggest that the ventral non-oscillatory regions are asymmetrically associated with non-motor functions, with the right ventral STN associated with emotional processing. These results suggest that DBS of the right ventral STN may be associated with beneficial or adverse emotional effects observed in PD patients and may relieve mental symptoms in other neurological and psychiatric diseases.
Ofek, K, Soreq H.  2013.  Cholinergic involvement and manipulation approaches in multiple system disorders. 11th International Meeting on Cholinesterases. 203(1):113-119. Abstract
Within the autonomic system, acetylcholine signaling contributes simultaneously and interactively to cognitive, behavioral, muscle and immune functions. Therefore, manipulating cholinergic parameters such as the activities of the acetylcholine hydrolyzing enzymes in body fluids or the corresponding transcript levels in blood leukocytes can change the global status of the autonomic system in treated individuals. Specifically, cholinesterase activities are subject to rapid and effective changes. The enzyme activity baseline increases with age and body mass index and depends on gender and ethnic origin. Also, the corresponding DNA (for detecting mutations) and RNA (for measuring specific mRNA transcripts) of cholinergic genes present individual variability. In leukocytes, acetylcholine inhibits the production of pro-inflammatory cytokines, suggesting relevance of cholinergic parameters to both the basal levels and to disease-induced inflammation. Inversely, acetylcholine levels increase under various stress stimuli, inducing changes in autonomic system molecules (e.g., pro-inflammatory cytokines) which can penetrate the brain; therefore, manipulating these levels can also effect brain reactions, mainly of anxiety, depression and pain. Additionally, neurodegenerative diseases often involve exacerbated inflammation, depression and anxiety, providing a focus interest group for cholinergic manipulations. In Alzheimer’s disease, the systemic cholinergic impairments reflect premature death of cholinergic neurons. The decline of cholinesterases in the serum of Parkinson’s disease and post- stroke patients, discovery of the relevant microRNAs and the growing range of use of anticholinesterase medications all call for critical re-inspection of established and novel approaches for manipulating cholinergic parameters.
Miyamichi, K, Shlomai-Fuchs Y, Shu M, Weissbourd B, Luo L, Mizrahi A.  2013.  Dissecting Local Circuits: Parvalbumin Interneurons Underlie Broad Feedback Control of Olfactory Bulb Output. Neuron. :-. Abstract
In the mouse olfactory bulb, information from sensory neurons is extensively processed by local interneurons before being transmitted to the olfactory cortex by mitral and tufted (M/T) cells. The precise function of these local networks remains elusive because of the vast heterogeneity of interneurons, their diverse physiological properties, and their complex synaptic connectivity. Here we identified the parvalbumin interneurons (PVNs) as a prominent component of the M/T presynaptic landscape by using an improved rabies-based transsynaptic tracing method for local
Labarrera, C, London M, Angelo K.  2013.  Tonic inhibition sets the state of excitability in olfactory bulb granule cells. The Journal of Physiology. 591(7):1841-1850. Abstract
• Granule cells are the main source of inhibition in the olfactory bulb (i.e. the first station of odour processing in the mammalian brain), but very little is known about the inhibition that acts upon them.• Using in vivo whole cell patch clamp recordings in anaesthetized mice we report the following new findings:• We found odour-evoked responses to be rare (seen only in 18% of the odour presentations, and only in cells that showed also evoked excitatory responses to odours).• We report for the first time the presence of tonic inhibition in the olfactory bulb.• We show that tonic inhibition dominates over phasic synaptic inhibition evoked by odours, thereby being the key regulator shaping the granule cells spike output.• Preliminary (in vivo) evidence suggests that sensory evoked phasic inhibition onto granule cells is provided by deep short axon cells in the olfactory bulb.GABAergic granule cells (GCs) regulate, via mitral cells, the final output from the olfactory bulb to piriform cortex and are central for the speed and accuracy of odour discrimination. However, little is known about the local circuits in which GCs are embedded and how GCs respond during functional network activity. We recorded inhibitory and excitatory currents evoked during a single sniff-like odour presentation in GCs in vivo. We found that synaptic excitation was extensively activated across cells, whereas phasic inhibition was rare. Furthermore, our analysis indicates that GCs are innervated by a persistent firing of deep short axon cells that mediated the inhibitory evoked responses. Blockade of GABAergic synaptic input onto GCs revealed a tonic inhibitory current mediated by furosemide-sensitive GABAA receptors. The average current associated with this tonic GABAergic conductance was 3-fold larger than that of phasic inhibitory postsynaptic currents. We show that the pharmacological blockage of tonic inhibition markedly increased the occurrence of supra-threshold responses during an odour-stimulated sniff. Our findings suggest that GCs mediate recurrent or lateral inhibition, depending on the ambient level of extracellular GABA.
Nelken, I, de Cheveigne A.  2013.  An ear for statistics. Nature Neuroscience.. 16(4):381-382.
Adler, A, Finkes I, Katabi S, Prut Y, Bergman H.  2013.  Encoding by Synchronization in the Primate Striatum. The Journal of Neuroscience. 33(11):4854-4866. Abstract
Information is encoded in the nervous system through the discharge and synchronization of single neurons. The striatum, the input stage of the basal ganglia, is divided into three territories: the putamen, the caudate, and the ventral striatum, all of which converge onto the same motor pathway. This parallel organization suggests that there are multiple and competing systems in the basal ganglia network controlling behavior. To explore which mechanism(s) enables the different striatal domains to encode behavioral events and to control behavior, we compared the neural activity of phasically active neurons [medium spiny neurons (MSNs), presumed projection neurons] and tonically active neurons (presumed cholinergic interneurons) across striatal territories from monkeys during the performance of a well practiced task. Although neurons in all striatal territories displayed similar spontaneous discharge properties and similar temporal modulations of their discharge rates to the behavioral events, their correlation structure was profoundly different. The distributions of signal and noise correlation of pairs of putamen MSNs were strongly shifted toward positive correlations and these two measures were correlated. In contrast, MSN pairs in the caudate and ventral striatum displayed symmetrical, near-zero signal and noise correlation distributions. Furthermore, only putamen MSN pairs displayed different noise correlation dynamics to rewarding versus neutral/aversive cues. Similarly, the noise correlation between tonically active neuron pairs was stronger in the putamen than in the caudate. We suggest that the level of synchronization of the neuronal activity and its temporal dynamics differentiate the striatal territories and may thus account for the different roles that striatal domains play in behavioral control.
Taubman, H, Vaadia E, Paz R, Chechik G.  2013.  A Bayesian approach for characterizing direction tuning curves in the supplementary motor area of behaving monkeys. Journal of Neurophysiology. Abstract
Neural responses are commonly studied in terms of "tuning curves", characterizing changes in neuronal response as a function of a continuous stimulus parameter. In the motor system, neural responses to movement-direction often follow a bell-shaped tuning curve, whose exact shape determines the properties of neuronal movement coding. Estimating the shape of that tuning curve robustly is hard, especially when directions are sampled unevenly and at a coarse resolution. Here we describe a Bayesian estimation procedure that improves the accuracy of curve-shape estimation, even when the curve is sampled unevenly and at a very coarse resolution. Using this approach we characterize the movement direction tuning curves in the supplementary motor area (SMA) of behaving monkeys. We compare the SMA tuning curves to tuning curves of neurons from the primary motor cortex (M1) of the same monkeys, showing that the tuning curves of the SMA neurons tend to be narrower and shallower. We also show that these characteristics do not depend on the specific location in each region.
Soreq, L, Bergman H, Israel Z, Soreq H.  2013.  OVERLAPPING MOLECULAR SIGNATURES IN PARKINSON'S PATIENT LEUKOCYTES BEFORE AND AFTER TREATMENT AND IN MOUSE MODEL BRAIN REGIONS.. CNS & neurological disorders drug targets. Abstract
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease with worldwide increasing incidence. PD is the second most prevalent neurodegenerative disease and the first that involves motor symptoms. The great majority of cases, defined as sporadic with non-familial disease, show a highly variable risk of disease due to environmental and genetic factors that remain largely unknown. Furthermore, the neurodegenerative process typically initiates decades prior to the appearance of hallmark motor symptoms; therefore, clinical diagnosis is enabled only when most of the relevant neurons have died and current treatment is palliative at best. Here, we review the application of genomic scale microarray based research aimed to enable early diagnosis and identify novel targets for therapeutic intervention. We demonstrate that blood leukocytes can serve as a feasible and reliable tissue source to test for disease-induced and treatment-related transcript changes. We cover our reports of transcription and alternative splicing modifications in PD patient's leukocytes based on 3' and exon microarray analyses and the identified inflammatory modulations. We further describe the effects of deep brain stimulation (DBS) neurosurgery on the leukocyte transcripts as reflecting the patient's neurological status. A focus is gained on common genes identified both in the molecular signature of human PD leukocytes and in brain RNA from engineered PD mouse models subjected to risk and protection manipulations. Finally, we discuss potential future directions of high-throughput RNA research as facilitators of the PD knowledge base through next generation sequencing technologies of both short and long RNA transcripts including microRNAs.
Weizman, L, Helfer D, Ben Bashat D, Pratt L-T, Joskowicz L, Constantini S, Shofty B, Ben Sira L.  2013.  PNist: interactive volumetric measurements of plexiform neurofibromas in MRI scans.. International journal of computer assisted radiology and surgery. Abstract
Volumetric measurements of plexiform neurofibromas (PNs) are time consuming and error prone, as they require the delineation of the PN boundaries, which is mostly impractical in the daily clinical setup. Accurate volumetric measurements are seldom performed for these tumors mainly due to their great dispersion, size and multiple locations. This paper presents a semiautomatic method for segmentation of PN from STIR MRI scans.
Maharshak, N, Shenhar-Tsarfaty S, Aroyo N, Orpaz N, Guberman I, Canaani J, Halpern Z, Dotan I, Berliner S, Soreq H.  2013.  MicroRNA-132 Modulates Cholinergic Signaling and Inflammation in Human Inflammatory Bowel Disease.. Inflammatory bowel diseases. 19(7):1346-53. Abstract
: MicroRNA-132 (miR-132) targets acetylcholinesterase (AChE) and potentiates the cholinergic blockade of inflammatory reactions in cultured cells and experimental mice, but the implications of this interaction to human inflammatory disease remained unexplored. This study aimed to test whether miR-132 is causally involved in anti-inflammatory reactions of patients with inflammatory bowel disease (IBD) and modulates vagal tone and consequently inflammation in patients with IBD.
Rothschild, G, Cohen L, Mizrahi A, Nelken I.  2013.  Elevated correlations in neuronal ensembles of mouse auditory cortex following parturition.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(31):12851-61. Abstract
The auditory cortex is malleable by experience. Previous studies of auditory plasticity have described experience-dependent changes in response profiles of single neurons or changes in global tonotopic organization. However, experience-dependent changes in the dynamics of local neural populations have remained unexplored. In this study, we examined the influence of a dramatic yet natural experience in the life of female mice, giving birth and becoming a mother on single neurons and neuronal ensembles in the primary auditory cortex (A1). Using in vivo two-photon calcium imaging and electrophysiological recordings from layer 2/3 in A1 of mothers and age-matched virgin mice, we monitored changes in the responses to a set of artificial and natural sounds. Population dynamics underwent large changes as measured by pairwise and higher-order correlations, with noise correlations increasing as much as twofold in lactating mothers. Concomitantly, changes in response properties of single neurons were modest and selective. Remarkably, despite the large changes in correlations, information about stimulus identity remained essentially the same in the two groups. Our results demonstrate changes in the correlation structure of neuronal activity as a result of a natural life event.
Rothschild, G, Cohen L, Mizrahi A, Nelken I.  2013.  Elevated correlations in neuronal ensembles of mouse auditory cortex following parturition.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(31):12851-61. Abstract
The auditory cortex is malleable by experience. Previous studies of auditory plasticity have described experience-dependent changes in response profiles of single neurons or changes in global tonotopic organization. However, experience-dependent changes in the dynamics of local neural populations have remained unexplored. In this study, we examined the influence of a dramatic yet natural experience in the life of female mice, giving birth and becoming a mother on single neurons and neuronal ensembles in the primary auditory cortex (A1). Using in vivo two-photon calcium imaging and electrophysiological recordings from layer 2/3 in A1 of mothers and age-matched virgin mice, we monitored changes in the responses to a set of artificial and natural sounds. Population dynamics underwent large changes as measured by pairwise and higher-order correlations, with noise correlations increasing as much as twofold in lactating mothers. Concomitantly, changes in response properties of single neurons were modest and selective. Remarkably, despite the large changes in correlations, information about stimulus identity remained essentially the same in the two groups. Our results demonstrate changes in the correlation structure of neuronal activity as a result of a natural life event.