Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Neuromodulatory Systems -- Recent Research



Science 16 October 2009:  Vol. 326. no. 5951, pp. 449 - 453

Fast Synaptic Subcortical Control of Hippocampal Circuits

Viktor Varga,1 Attila Losonczy,2 Boris V. Zemelman,2 Zsolt Borhegyi,1 Gábor Nyiri,1 Andor Domonkos,1 Balázs Hangya,1 Noémi Holderith,1 Jeffrey C. Magee,2 Tamás F. Freund1

1 Institute of Experimental Medicine, Budapest 1083, Hungary.
2 Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, VA 20147, USA.

Cortical information processing is under state-dependent control of subcortical neuromodulatory systems. Although this modulatory effect is thought to be mediated mainly by slow nonsynaptic metabotropic receptors, other mechanisms, such as direct synaptic transmission, are possible. Yet, it is currently unknown if any such form of subcortical control exists. Here, we present direct evidence of a strong, spatiotemporally precise excitatory input from an ascending neuromodulatory center. Selective stimulation of serotonergic median raphe neurons produced a rapid activation of hippocampal interneurons. At the network level, this subcortical drive was manifested as a pattern of effective disynaptic GABAergic inhibition that spread throughout the circuit. This form of subcortical network regulation should be incorporated into current concepts of normal and pathological cortical function.

Subcortical monoaminergic systems are traditionally thought to modulate target cortical networks on a slow time scale of hundreds of milliseconds to seconds corresponding to the duration of metabotropic receptor signaling. Among these ascending systems, the serotonergic raphe-hippocampal (RH) pathway that primarily originates within the midbrain median raphe nucleus (MnR) is a key modulator of hippocampal mnemonic functions. Contrary to the slow modulatory effect commonly associated with ascending systems, electrical stimulation of the RH pathway produces a rapid and robust modulation of hippocampal electroencephalographic activity. Anatomical evidence shows that MnR projections form some classical synapses onto GABAergic interneurons (INs) in the hippocampus, potentially providing a substrate for a fast neuromodulation of the hippocampal circuit. Recent reports of the presence of glutamate in the serotonergic system raise the possibility that this system may use a coordinated action of serotonin [5-hydroxytryptamine (5-HT)] and glutamate to rapidly activate elements of the hippocampal network.

The present demonstration of a fast synaptic activation of hippocampal interneurons by MnR afferents via glutamate/serotonin cotransmission puts the subcortical control of cortical information processing in a fundamentally new perspective. The current view of a slow and diffuse modulation conveying emotional, motivational, or other state-dependent tuning is now complemented by the ability to carry out target-selective synaptic actions with high temporal and spatial resolution. This additional ability may promote the rapid formation and selection of particular hippocampal local representations or modes of information processing, possibly through fast alterations in the relative contribution of the different classes of interneurons to rhythmic population activity. Finally, the present observations lend support to a proposed role of glutamate in disorders that have traditionally been considered to be subcortical in origin, such as depression, anxiety, and certain components of schizophrenia.


Science 12 June 2009: Vol. 324. no. 5933, pp. 1441 - 1444

Fluorescent False Neurotransmitters Visualize Dopamine Release from Individual Presynaptic Terminals

Niko G. Gubernator,1 Hui Zhang,2,3 Roland G. W. Staal,2 Eugene V. Mosharov,2 Daniela B. Pereira,2 Minerva Yue,2 Vojtech Balsanek,1 Paul A. Vadola,1 Bipasha Mukherjee,4 Robert H. Edwards,4 David Sulzer,2,3,5 Dalibor Sames1

1 Department of Chemistry, Columbia University, New York, NY 10027, USA.
2 Departments of Neurology, Psychiatry, and Pharmacology, Columbia University, New York, NY 10032, USA.
3 Departments of Psychiatry and Pharmacology, Columbia University, New York, NY 10032, USA.
4 Departments of Neurology and Physiology, University of California School of Medicine, San Francisco, San Francisco, CA 94143, USA.
5 Division of Molecular Therapeutics, New York Psychiatric Institute, New York, NY 10032, USA.

The nervous system transmits signals between neurons via neurotransmitter release during synaptic vesicle fusion. In order to observe neurotransmitter uptake and release from individual presynaptic terminals directly, we designed fluorescent false neurotransmitters as substrates for the synaptic vesicle monoamine transporter. Using these probes to image dopamine release in the striatum, we made several observations pertinent to synaptic plasticity. We found that the fraction of synaptic vesicles releasing neurotransmitter per stimulus was dependent on the stimulus frequency. A kinetically distinct "reserve" synaptic vesicle population was not observed under these experimental conditions. A frequency-dependent heterogeneity of presynaptic terminals was revealed that was dependent in part on D2 dopamine receptors, indicating a mechanism for frequency-dependent coding of presynaptic selection.

Decision making, memory, and learning require activation and modification of particular synapses. Synaptic transmission in turn requires neurotransmitter accumulation into synaptic vesicles followed by neurotransmitter release during synaptic vesicle fusion with the plasma membrane.

We designed optical tracers of monoamine neurotransmitters, or fluorescent false neurotransmitters (FFNs), inspired by classic reports that tyramine, amphetamine, and other phenylethylamines can be taken up into secretory vesicles and discharged during exocytosis. We designed FFNs by targeting neuronal vesicular monoamine transporter 2 (VMAT2), which carries monoamine neurotransmitters from the cytoplasm into synaptic vesicles. VMAT2 is relatively nonspecific and transports cellular monoamines (such as dopamine, serotonin, and norepinephrine) as well as synthetic amines (such as amphetamine).

We analyzed the heterogeneity within large ensembles of dopamine terminals in the striatum. The spatial distribution of presynaptic activity appeared to be complex, with very active and inactive terminals often nearby.

Presynaptic terminal heterogeneity is stimulation frequency–dependent, although we cannot exclude the possibility that this is due to differences in axonal action potential propagation.

Spatial heterogeneity of dopamine release has been demonstrated by means of electrochemical recordings with a resolution of ~100 µm and has been suggested to play an important role in the modulation of synaptic circuitry involved in motivation, reward, and learning.

FFNs enable optical measurements of key presynaptic processes in the central nervous system, including accumulation of a vesicle transporter substrate and release by evoked activity or drugs such as amphetamine, at unprecedented spatial resolution. FFN511 is compatible with GFP-based tags and other optical probes, which allow the construction of fine-resolution maps of synaptic microcircuitry and presynaptic activity, particularly in regions such as the hippocampus and cortex where monoamine innervation can be too sparse for electrochemical recording.



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