Investigating striatal function through cell-type-specific manipulations.

The striatum integrates convergent input from the cortex, thalamus, and midbrain, and has a powerful influence over motivated behavior via outputs to downstream basal ganglia nuclei. Although the anatomy and physiology of distinct classes of striatal neurons have been intensively studied, the specific functions of these cell subpopulations have been more difficult to address. Recently, application of new methodologies for perturbing activity and signaling in different cell types in vivo has begun to allow direct tests of the causal roles of striatal neurons in behavior.

State-dependent plasticity of the corticostriatal pathway.

Plasticity at corticostriatal synapses is thought to underlie both normal and aberrant forms of reinforcement-driven learning. Studies in brain slices have found bidirectional, spike-timing dependent plasticity in striatum; however it is not known whether similar rules govern corticostriatal plasticity in awake behaving animals. To assess whether behavioral state is a key regulator of plasticity in this pathway, we examined the effects of 5 Hz cortical stimulation trains on evoked striatal field potentials, in either anesthetized or awake, unrestrained rats. Consistent with prior studies we observed long-term potentiation in intact, barbiturate-anesthetized animals. However, when an identical stimulation pattern was applied to the same animals while awake, long-term depression was observed instead. Our results demonstrate that the rules governing corticostriatal plasticity depend critically on behavioral state, and suggest that the dynamic context of cortical-basal ganglia loops must be considered while investigating synaptic mechanisms underlying reinforcement learning and neurological disorders.

Fast oscillations in cortical-striatal networks switch frequency following rewarding events and stimulant drugs.

Oscillations may organize communication between components of large-scale brain networks. Although gamma-band oscillations have been repeatedly observed in cortical-basal ganglia circuits, their functional roles are not yet clear. Here I show that, in behaving rats, distinct frequencies of ventral striatal local field potential oscillations show coherence with different cortical inputs. The approximately 50 Hz gamma oscillations that normally predominate in awake ventral striatum are coherent with piriform cortex, whereas approximately 80-100 Hz high-gamma oscillations are coherent with frontal cortex. Within striatum, entrainment to gamma rhythms is selective to fast-spiking interneurons, with distinct fast-spiking interneuron populations entrained to different gamma frequencies. Administration of the psychomotor stimulant amphetamine or the dopamine agonist apomorphine causes a prolonged decrease in approximately 50 Hz power and increase in approximately 80-100 Hz power. The same frequency switch is observed for shorter epochs spontaneously in awake, undrugged animals and is consistently provoked for < 1 s following reward receipt. Individual striatal neurons can participate in these brief high-gamma bursts with, or without, substantial changes in firing rate. Switching between discrete oscillatory states may allow different modes of information processing during decision-making and reinforcement-based learning, and may also be an important systems-level process by which stimulant drugs affect cognition and behavior.

Functional clustering algorithm for the analysis of dynamic network data.

We formulate a technique for the detection of functional clusters in discrete event data. The advantage of this algorithm is that no prior knowledge of the number of functional groups is needed, as our procedure progressively combines data traces and derives the optimal clustering cutoff in a simple and intuitive manner through the use of surrogate data sets. In order to demonstrate the power of this algorithm to detect changes in network dynamics and connectivity, we apply it to both simulated neural spike train data and real neural data obtained from the mouse hippocampus during exploration and slow-wave sleep. Using the simulated data, we show that our algorithm performs better than existing methods. In the experimental data, we observe state-dependent clustering patterns consistent with known neurophysiological processes involved in memory consolidation.

Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin.

Control of neuronal gene expression by drugs or neurotransmitters is a critical step in long-term neural plasticity. Here, we show that a gene induced in the striatum by cocaine or direct dopamine stimulation, ania-6, is a member of a novel family of cyclins with homology to cyclins K/T/H/C. Further, different types of neurotransmitter stimulation cause selective induction of distinct ania-6 isoforms, through alternative splicing. The longer Ania-6 protein colocalizes with nuclear speckles and is associated with key elements of the RNA elongation/processing complex, including the hyperphosphorylated form of RNA polymerase II, the splicing factor SC-35, and the p110 PITSLRE cyclin-dependent kinase. Distinct types of neuronal stimulation may therefore differentially modulate nuclear RNA processing, through altered transcription and splicing of ania-6.

A complex program of striatal gene expression induced by dopaminergic stimulation.

Dopamine acting in the striatum is necessary for normal movement and motivation. Drugs that change striatal dopamine neurotransmission can have long-term effects on striatal physiology and behavior; these effects are thought to involve alterations in gene expression. Using the 6-hydroxydopamine lesion model of Parkinson's disease and differential display PCR, we have identified a set of more than 30 genes whose expression rapidly increases in response to stimulation of striatal dopamine D1 receptors. The induced mRNAs include both novel and previously described genes, with diverse time courses of expression. Some genes are expressed at near-maximal levels within 30 min, whereas others show no substantial induction until 2 hr or more after stimulation. Some of the induced genes, such as CREM, CHOP, and MAP kinase phosphatase-1, may be components of a homeostatic response to excessive stimulation. Others may be part of a genetic program involved in cellular and synaptic plasticity. A very similar set of genes is induced in unlesioned animals by administration of the psychostimulant cocaine or the antipsychotic eticlopride, although in distinct striatal cell populations. In contrast to some previously described early genes, most of the novel genes are not induced in cortex by apomorphine, indicating specificity of induction. Thus we have identified novel components of a complex, coordinated genetic program that is induced in striatal cells in response to various dopaminergic manipulations.

Acute effects of cocaine on human brain activity and emotion.

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.

Antithetical meanings of 'the breast'.

This paper addresses the issue of the antithetical meaning of primary words, and, in particular, it considers the primary word and concept, 'the breast'. The authors point out that many languages convey some aspects of the complicated, convoluted and contradictory significance of 'the breast'. But none does so better than Hebrew, which is a central member of the Semitic group of languages. Consequently, the authors have chosen to explore the diverse significance of the term 'breast', by tracing the derivations of the Hebrew bilateral root for breast which is, 'shahd'. In doing so they show that the many linguistic transformations discussed are clearly in line with Freud's discussion of dream processes as well as his interest in the reversal and reduplication of root words. Perhaps, even more importantly, the paper demonstrates that by understanding the development of primary words it is possible to gain a closer, multidimensional appreciation of reality.

NMDA potentiates NGF-induced sprouting of septal cholinergic fibres.

Nerve growth factor (NGF) injected into the otherwise unlesioned adult rat septum induced sprouting of presumptive cholinergic fibres positive for p75NGFR and acetylcholinesterase (AChE). These fibres did not stain for tyrosine hydroxylase and therefore did not represent sympathetic ingrowth. Neurofilament staining on adjacent sections revealed fibres with similar morphology, suggesting new outgrowth in the form of sprouting rather than the upregulation of p75NGFR and AChE in pre-existing fibres. Simultaneous injections of subneurotoxic doses of N-methyl-D-aspartate (NMDA) significantly potentiated the effect of NGF on cholinergic fibre sprouting and caused pronounced glial fibrillary acidic protein (GFAP)-positive astrocytosis. Application of NMDA alone did not elicit sprouting of this type. These findings indicate that NGF can induce the sprouting of uninjured adult rat septal cholinergic fibres in vivo and suggest that reactive astrocytes are not inhibitory to cholinergic axonal outgrowth, and might serve as a substrate for growing axons in the presence of NGF.

Cytologic examination of the nasal mucosa in formaldehyde-exposed workers.

A cross-sectional study of 80 individuals at three locations was undertaken to evaluate the health effects of long-term exposure to formaldehyde in a phenol-formaldehyde impregnating process and to develop a useful protocol for health surveillance of formaldehyde-exposed workers. Results of physical examinations showed a statistically significant prevalence of mucosal irritation in formaldehyde-exposed workers, particularly those with recent exposure. Cytologic examination of exfoliated nasal cells showed atypical squamous metaplasia, which was found to be a function of age. There was no statistical relationship to formaldehyde exposure.

Arriving, settling-in, settling-down, leaving and following-up: stages of stay at the Arbours Centre.

The Arbours Centre is a small psychodynamically oriented therapeutic community which accommodates three live-in psychotherapists and up to five 'guests' at any one time. This paper describes the 'stages of stay' which guests and therapists pass through during the course of an intervention at the Centre, and discusses their interactions during each of these periods.