Abstracts and References:

Yuji Ikegaya
"Latent stereotypy and metastability in spontaneous activity in the neocortex"

The organization and potential function of the cortical microcircuit are poorly understood. Because spontaneous neuronal activity is prevalent in vivo and in vitro and could reflect intrinsic functional properties of the cortical microcircuit, its dynamics may help reveal basic features of the function and logic of the cortex. We monitored action potential-evoked calcium transients of about 1,000 cortical neurons in vitro for a period of up to 20 min to reconstruct the spatiotemporal dynamics of pontaneous activity. We found that some sequences of activity were reactivated in the same spatiotemporal order. Spontaneous activity drifts with time, recruiting different sets of cells, and thereby sequences are replaced with novel patterns; most sequences were repeated only twice, and the inter-repetition interval was less than 30 sec. Patterns of spontaneous activity can be predicated by using a past period of data as a training set for an autoassociative neural network model. Activity patterns during sequence-rich states are more accurately predicted than that during sequence-poor states. Based on the connection weights between neurons in the neural network that learned spontaneous activity in datasets, we reconstructed cell assembly organizations in the cortical microcircuit to reveal putative circuit architectures that can produce activity repetitions. Our data demonstrate reverberating patterns of spontaneous activity and underscore the importance of precise temporal dynamics in cortical function.

Ikegaya Y, Aaron G, Cossart R, Aronov D, Lampl I, Ferster D, Yuste R. (2004) Synfire chains and cortical songs: temporal modules of cortical activity. Science. Apr 23;304(5670):559-64.

Abeles M. (2004) Time is precious. Science. Apr 23;304(5670):523-4.

Kazutoshi Nakazawa
"The roles of hippocampal NMDA receptors in learning and Memory"

N-methyl-D-aspartate receptors (NRs) in the hippocampus have been shown to be essential for learning and memory, and for long-term synaptic plasticity at a variety of hippocampal synapses. Here I summarize the current evidence concerning the role of NRs in hippocampal memory processes, with an emphasis on the function of CA1 NRs in memory acquisition, and the unique role of CA3 NRs in the rapid acquisition and associative retrieval of spatial information. I also discuss the data that have emerged from in vivo hippocampal recording studies that indicate that the activity of hippocampal place cells during behavior is an expression of a memory trace.

Nakazawa K, McHugh TJ, Wilson MA, Tonegawa S. (2004) NMDA receptors, place cells and hippocampal spatial memory. Nature Review Neuroscience. May;5(5):361-72.

＊PDF is available: http://www.neuroscience.nih.gov/Lab.asp?Org_ID=496

Barry Richmond
"Dopamine-dependent associative learning of cues predicting work-load before reward in the monkey"

Learning to react to external stimuli within one or a few exposures to them is an amazing feature of normal behavior. For example, to interpret visual stimuli, the stimuli must become associated with the predicted outcome for subsequent events, be they actions the animals control or not. To examine this ability we have been studying how monkeys interpret visual cues as they try to balance the desire to obtain a reward with the need to work (an aversiveness condition) to obtain it. We have learned that many dopamine-rich brain regions (including ventral striatum, anterior cingulate cortex, and others) have signals related to this ability. We use behavioral control, single neuronal recording, selective brain ablation, and finally a new technique to manipulate single molecules in specific brain areas, to establish that rhinal cortex (perirhinal plus entorhinal cortices) is critical for learning to associate visual cues with predictions of the workload remaining to! obtain a reward. I will review the evidence establishing this finding. I will then focus on experiments using this new molecular tool that we have used to show that the D2 receptor in the rhinal cortex is essential for learning the cue-workload associations.

A fundamental tenant of the scientific method is to connect one level of natural function to another, often by manipulating one level and observing the effect of the manipulation on the other level. In general, we seek to identify causal relations. The remarkable discoveries in molecular biology over the past 2/3 of a century have held the promise of such methods. A time is approaching when we as a community can take advantage of these new and very specific approaches. The technique we have developed is based on the use of antisense expression vectors as a relatively long-lived (weeks), yet naturally reversible, molecular lesions. Other approaches with other advantages and disadvantages are under development in other labs. The motivation for developing these techniques is to allow closer correlation of different levels of manipulation and/or observation.

Liu Z, Richmond B, Murray E, Saunders R, Steenrod S, Stubblefield B, Montague D, and Ginns E (2004) DNA targeting of rhinal cortex D2 receptor protein reversibly blocks learning of cues that predict reward. Proceedings of the National Academy of Sciences (PNAS) Vol. 101, No. 33: 12336-12341. August 17, 2004.

Murray E, Richmond B (2001) Role of perirhinal cortex in object perception, memory, and associations. Current Opinion in Neurobiology 11: 188-193.

Liu Z, Murray E, Richmond B (2000) Learning motivational significance of visual cues for reward schedules requires rhinal cortex. Nature Neuroscience Vol. 3, No. 12, 1307-1515.

Shidara M, Richmond B (2002) Anterior Cingulate: Single Neuronal Signals Related to Degree of Reward Expectancy. Science. Vol. 296: 1709-1711.

＊PDFs are available: http://richmond.nimh.nih.gov/richmond.html, numbers 17, 9, 10, 14.

Jeff Wickens
"Dopamine-related plasticity in the striatum and its contribution to cortical-basal ganglia function"

Alongside an established role in motor activation, the basal ganglia are increasingly recognised as playing a crucial role in integrative behaviour, although the precise nature of this role remains to be elucidated.The basal ganglia may play a particular role in learning on the basis of positive reinforcement. The striatum - the input nucleus of the basal ganglia - is a locus for interaction of neural signals (from the cerebral cortex) reflecting the current situation of the organism, positive reinforcement (from the midbrain dopamine neurons), and behavioural output (via the motor cortex). Dopamine-related plasticity in the synaptic connections between the cerebral cortex and striatum may underpin the strengthening of associations between situations and actions, providing a neural mechanism for learning. In the context of corticostriatal interactions, this mechanism may contribute to learning which actions lead to favourable outcomes.

Reynolds JN, Hyland BI, Wickens JR. (2001) A cellular mechanism of reward-related learning. Nature. 2001 Sep 6;413(6851):67-70.

Wickens JR, Reynolds JN, Hyland BI. (2003) Neural mechanisms of reward-related motor learning. Current Opinion in Neurobiology. 2003 Dec;13(6):685-90. Review.

Pan WX, Schmidt R, Wickens JR, Hyland BI. (2005) Dopamine cells respond to predicted events during classical conditioning: evidence for eligibility traces in the reward-learning network. Journal of Neuroscience. 2005 Jun 29;25(26):6235-42.

Reynolds JN, Hyland BI, Wickens JR. (2004) Modulation of an afterhyperpolarization by the substantia nigra induces pauses in the tonic firing of striatal cholinergic interneurons. Jornal of Neuroscience. 2004 Nov 3;24(44):9870-7.

James Tepper
"Feedforward and Feedback GABAergic Inhibition in Neostriatum"

Intrastriatal GABAergic signaling comprises feedforward pathways, mediated by at least 3 classes of GABAergic interneurons, and feedback pathways, arising from the axon collaterals of the spiny projection neurons. The spiny cell axon collaterals have long been assumed to be the substrates of a widespread lateral inhibitory network, often modeled with winner-take-all dynamics. However, results from recent electrophysiological studies, that for the first time directly compared the characteristics of interneuronal inhibition with those of collateral inhibition, are incompatible with this view. The feedforward pathways are strong and single interneurons exert powerful effects on spike timing in spiny neurons, whereas the axon collateral connections are relatively weak, and lack the reciprocal connectivity needed to underlie the types of strong lateral inhibition previously assumed. These data will be reviewed and used to suggest a modified view of the functional roles of GABAergic inhibition in the neostriatum.

Tepper JM, Koos T, Wilson CJ. (2004) GABAergic microcircuits in the neostriatum. Trends in Neuroscience. 2004 Nov;27(11):662-9. Review.

Koos T, Tepper JM, Wilson CJ. (2004) Comparison of IPSCs evoked by spiny and fast-spiking neurons in the neostriatum. Journal of Neuroscience. 2004 Sep 8;24(36):7916-22.

Tepper JM, Bolam JP. (2004) Functional diversity and specificity of neostriatal interneurons. Current Opinion in Neurobiology. 2004 Dec;14(6):685-92. Review.

Kenji Doya
"Prediction of future rewards in the striatum and its modulation by serotonin"

What it the brain mechanism that allow us to learn a variety of behaviors to achieve goals in unknown environments? The basal ganglia and dopaminergic system appear to play a critical role in acquisition of novel behaviors based on reward feedback. The theory of reinforcement learning, reward-based learning can be realized by following the three steps: 1) predict reward for each action candidate; 2) select and action with the higher predicted reward at a higher probability 3) update the prediction according to the difference between the prediction and actual outcome. We are exploring how these three major steps are implemented in the circuit of the basal ganglia, and how the learning process is regulated by the neuromodulator systems, such as dopamine and serotonin.

We first show neuron recording experiments showing that many striatal neurons represent 'action value,' the expected reward for each action candidate. We then report our functional brain imaging results suggesting that there are parallel cortico-basal ganglia pathways that are specialized for future reward prediction at different time scales. Furthermore, through dietary regulation of tryptophan, the precursor of serotonin, we show that the parallel pathways are differentially regulated by serotonin, suggesting that enhancement of serotonergic function promotes reward prediction into the longer future, and its deficit results in impulsive behaviors.

Doya K. (2002). Metalearning and neuromodulation. Neural Networks, 15, 495-506.

Tanaka C. S., Doya K., Okada G., Ueda K., Okamoto Y., Yamawaki S. (2004). Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops. Nature Neuroscience, 7, 887-893.

＊PDFs are available: www.cns.atr.jp/￣doya/papers