The scientific interest of my research group is to better understand the neurophysiological mechanisms of noradrenergic (NA) neuromodulation in the brain. The NA system mediates many cognitive processes such as attention, perception, learning and memory. Dysfunction in noradrenergic system often leads to various psychiatric disorders.
The core of the NA system is a small brainstem nucleus Locus Coeruleus (LC). The LC-NA neurons project extensively throughout the brain, innervating the spinal cord, the brain stem, hypothalamus, cerebellum, thalamic relay nuclei, amygdala, basal telencephalon, as well as the cortex. As opposed to direct synaptic neurotransmission (wired transmission), the axons of NA neurons commonly have characteristic varicosities by means of which NA is secreted and diffused through large volumes of tissue (volume transmission), thereby affecting simultaneously multiple and diverse population of neurons. The mechanisms underlying the specificity of neuromodulatory effects at different projection targets are poorly understood. A major advance in understanding the neurophysiological mechanisms of NA neuromodulation in the brain may be achieved by monitoring neuromodulatory effects at multiple brain regions simultaneously and at different scales.
The specific aims are the following: 1) to describe the effective (functional) connectivity of the LC in the rat brain; 2) to characterize temporal interactions between LC activity and its cortical and subcortical targets during spontaneous and sensory-evoked activity in anesthetized and behaving rats; and 3) to study how the modulation of LC activity affects cortical state, sensory responses, and sensory-guided behavior.
Project 1. Mapping of the functional connectivity of the LC in the rat brain.
We compared the labeling produced by a classical anatomical tracer (fluorescent dextran) and by MRI-visible tracer (Mn2+) injected simultaneously in LC. The major cortical and subcortical targets of LC projections including predominantly ipsilateral primary motor (M1) and somatosensory (S1) cortices, hippocampus and amygdala were detected using manganese-enhanced MRI (MEMRI). MEMRI method consistently failed to reliably label several minor but also major targets of LC, notably the thalamus (Eschenko et al., 2011). The lack of Mn2+ labeling in thalamus possibly reflected a weaker functional connectivity within coeruleothalamic projections that could not be predicted by anatomical tracing. These results will be complemented by mapping of the functional connectivity of the LC projections using combined microstimulation and fMRI.
This project is collaboration with Dr. H.C. Evrard and R. Neves.
Eschenko O, Evrard HC, Neves RM, Beyerlein M, Murayama Y, Logothetis NK. (2011) Tracing of noradrenergic projections using manganese-enhanced MRI, NeuroImage, in print.
Project 2. Differential noradrenergic modulation in the rat somatosensory and prefrontal cortex.
We compared the effects of systemic (i.p.) or local (into LC) application of clonidine, an alpha2-receptor agonist, which is known to inhibit LC-NA neurons, on sensory responses in S1 and PFC, the two cortical targets of LC. Local application of clonidine resulted in complete cessation of both spontaneous and evoked activity of LC neurons to mild foot shocks (FS). Absence of LC signaling did not affect S1 responses, while both increased and decreased responses were observed in PFC (Fig.1). Systemic clonidine produced a transient decrease of LC spontaneous activity, while LC evoked responses were preserved. This manipulation decreased signal-to-noise ratio (SNR) in S1 neurons, while sensory signaling in PFC was, overall, increased. We now extend this project to recordings in VTA.
This project is collaboration with Dr. S. Sara and a part of the PhD study of S. van Keulen.
Project 3. Noradrenergic modulation of the cortical state and state-dependent sensory coding.
The neural responses to sensory stimulation are more robust when cortical activity is decorrelated (or desynchronized state). Moreover, the sensory responses markedly differ when stimulus occurred in the depolarized (Down) or hyperpolarized (Up) state. Inhibition of LC activity (e.g. by clonidine) leads to more synchronized activity in cortex. The electrical microstimulation of LC (e.g. trains of pulses at 50Hz for 500ms) applied during synchronized state produces a transient (~1-2s) desynchronization. The sensory responses resembled such during Up state if LC stimulation preceded the sensory stimulus.
This project is collaboration with Dr. S. Panzeri and Dr. C. Magri and a part of master thesis of R. Neves.
Project 4. Investigation of the effects of electrical microstimulation of the Locus Coeruleus in anesthetized and behaving rats.
We performed recording/stimulation unsing the same electrode tip placed in the LC. Electrical stimulation produced a sustained inhibition(40-120ms) of LC neurons at the stimulation site. There was no effect of pulse duration (range: 0.1-0.5ms) or current intensity (range: 0.01-0.2mA) on LC inhibition at the stimulation site. The linear relations between both factors and the duration of LC inhibitions were onserved at longer distances from the stimulation site. Neural responses in the contralateral LC showed overall a shorter inhibition (65±6ms). Trains of pulses (>200ms at 20-50Hz) delivered to the LC resulted in a transient desynchronization in mPFC.
This project is collaboration with Dr. A. Marzo.
Our results demonstrate that:
1) functional connectivity of LC with its projection targets could not be predicted from anatomical connectivity and may be context- or state dependent;
2) blocking the LC sensory-evoked discharge differentially affected signal processing in S1 and PFC as the opposite effects (decrease and increase in SNR) were observed with overall stronger modulation in PFC;
3) LC-NA system is involved in regulation of cortical state and therefore affect state-dependent sensory processing.
4) Application of the electrical current to LC, as low as 0.01mA, may mimic a characteristic response of the LC-NE neurons to salient stimuli (a brief excitation followed by a prolonged inhibition), however only a relatively strong LC stimulation (trains of pulses) affect neural activity in the distal cortical targets of LC, e.g. mPFC.
2006 present Max Planck Institute for Biological Cybernetics; Dept. Physiology of Cognitive Processes.
1999 PhD in Neurophysiology, Moscow State University, Moscow, Russia
2003-2006 Postdoctoral researcher at Dept. of Neuromodulation, Neuroplasticity & Cognition CNRS, UMR 7102; University Pierre & Marie Curie, Paris, France
2000-2003 Research assistant at Dept. of Psychology, University of Washington, Seattle, USA
1999-2000 Research fellow at Dept. of Pharmacology and Clinical Pharmacology, University of Turku, Finland