PietrajtisSLE2010 7 K Pietrajtis SJ Sara NK Logothetis O Eschenko Amsterdam, Netherlands2010-07-00 7th Forum of European Neuroscience (FENS 2010) The locus coeruleus (LC) and ventral tegmental area (VTA) are the source of noradrenergic and dopaminergic innervation of the medial prefrontal cortex (mPFC). These ascending projections to mPFC have been implicated in a broad range of cognitive processes in rodents and primates, but their relative contribution to mPFC function remains elusive. Determining temporal relations in spontaneous and evoked firing in the three regions is a necessary step toward understanding how the two neuromodulators might work in concert to regulate cognition. To this end, unit activity and local field potentials were recorded simultaneously from VTA, LC and mPFC. A number of electrophysiological and pharmacological criteria were used to identify VTA and LC neurons. After a period of recording of spontaneous activity, evoked responses were elicited by electrical shock to the hind paw. Shocks were single pulses (0.5ms, 5mA) or trains of 5 pulses, delivered at 50Hz. LC neurons responded to the single paw shock with a short latency ~ 20 ms, phasic burst, followed by brief inhibition. Trains elicited stronger responses, often biphasic, followed by prolonged inhibition. Most of the electrodes in the mPFC were located in the anterior cingulate area, where there was no response to single pulses. Trains elicited tonic excitatory responses with latencies of more than 100 ms, usually followed by inhibition, sometimes even entraining several cycles of slow oscillation. VTA neurons did not respond to the single pulse. Trains elicited excitatory responses in a small number of VTA cells, with latencies always greater than 100 ms. Both spontaneous and evoked activity of these VTA neurons was highly synchronised with mPFC activity; cortical activity always led VTA by several milliseconds. The results confirm that the LC neurons have a very low threshold and respond with a short latency to somatosensory stimulation. Corresponding release of noradrenaline will modulate sensory responses in the target regions including mPFC and VTA. The long response latency of the VTA cells suggests that its ascending projection does not play an important role in modulating mPFC response, but rather is driven by cortex and possibly modulated by LC. no notspecified http://www.kyb.tuebingen.mpg.de/ published 0 15017 15421 6814 7 O Eschenko K Pietrajtis SJ Sara NK Logothetis Santorini, Greece2010-06-00 60 AREADNE 2010: Research in Encoding And Decoding of Neural Ensembles Neural coding in medial prefrontal cortex (mPFC) is thought to underlie various cognitive behaviors such as rule-guided learning, strategy use, or cognitive flexibility. Specifically, prefrontal neurons display many behaviorally relevant correlates related to sensory perception, motor responses, or reward that are believed to contribute to behavioral outcome. The mPFC is the cortical region that receives exceptionally dense dopaminergic (DA) innervation arising from the mesopontine Ventral Tegmental Area (VTA). Noradrenergic fibers originating from the brain stem nucleus Locus Coeruleus (LC) are also dense in mPFC. Previous investigations indicated that NA and DA systems have common target neurons in mPFC. The ascending NA and DA projections to mPFC have been implicated in a broad range of cognitive processes in rodents and primates including modulation of perception, attention, motivation, or memory. It is still, however, unknown whether and how NA and DA affect the prefrontal neural codes. To address this question, we performed simultaneous recordings of unit activity and local field potentials in mPFC, VTA and LC in the rat. We first studied temporal relations of firing activity in the three brain regions during spontaneous and evoked activity under anesthesia. Mild electric shocks were applied to the rat hind paw for somatosensory stimulation. The LC neurons responded to a single foot shock (1ms, 5mA) with a short latency (~20ms), phasic burst, followed by brief inhibition. Trains of pulses (100ms, 50Hz, 5mA) elicited much stronger responses. The mPFC and VTA neurons did not respond to a single foot shock. Trains elicited sustained (~1s) excitatory responses in a subpopulation of mPFC neurons with latencies of ~100ms, usually followed by inhibition. Trains elicited both excitatory and inhibitory responses in a small number of putative dopaminergic, VTA cells, with latencies always greater than 100ms. Both spontaneous and evoked activity of VTA neurons was highly synchronized with mPFC activity; cortical activity always led VTA by several milliseconds. In some cases, sensory stimulation resulted in entrainment of mPFC and VTA neurons in several cycles of slow oscillation. Next, we inhibited the LC by systemic or local application of clonidine, an α2-adrenergic receptor agonist. This manipulation dramatically abolished the excitatory evoked responses in both VTA and mPFC without having much effect on spontaneous activity. The results indicate that short-latency responses of LC neurons to somatosensory stimulation with corresponding release of NA modulate sensory responses in the target regions including mPFC and VTA. The long-latency responses of the VTA cells suggest that its ascending projections do not play an important role in modulating mPFC responses to noxious stimuli. VTA activity is rather driven by mPFC and, possibly, modulated by LC. We will further investigate NA modulation of mPFC codes in the rat performing a prefrontaldependent task. To induce release of NA in mPFC, we will apply electrical microstimulation to the LC just before presentation of discrimination stimuli, mimicking the burst activity of LC typically observed in response to salient stimuli. We expect to see more robust coding in the mPFC correlated with better behavioral performance in the presence of LC activation. no notspecified http://www.kyb.tuebingen.mpg.de/ published -60 15017 15421 PietrajtisSLE2009 7 K Pietrajtis SJ Sara NK Logothetis O Eschenko Ellwangen, Germany2009-11-00 27 10th Conference of Junior Neuroscientists of Tübingen (NeNa 2009) Several investigations suggest that dopaminergic and noradrenergic neuromodulatory systems may simultaneously modulate their common targets. Moreover, the midbrain ventral tegmental area (VTA) and brain stem nucleus locus coeruleus (LC), the major sources of forebrain dopamine and noradrenaline, respectively, are reciprocally connected. The latter suggests that these two systems may be functionally interdependent. The aim of our experiments was to characterize spontaneous and evoked activity of these two neuromodulatory centers in parallel with monitoring neural activity in the medial prefrontal cortex (mPFC), their common projection structure. All experiments were performed in rats under urethane anesthesia. We recorded unit activity and local field potentials simultaneously from VTA, LC and mPFC. A number of electrophysiological and pharmacological criteria were used to distinguish VTA and LC neurons. Evoked activity was induced by a mild electrical stimulation of the hind paw. We also applied intrabrain microstimulation technique for VTA or LC regions and tested neural responses in mPFC. First, we observed a burst-like activation of LC neurons in response to hind paw stimulation with the response latency 20 ms. Brief LC activation followed by a prolonged (300 ms) inhibition. VTA neurons showed inhibitory response to the hind paw stimulation, but only if stimulation parameters were substantially stronger compared to those that activated LC (e. g. trains of pulses at 50 Hz for 100 ms). The preliminary results have not yet revealed any strong temporal relationships between spontaneous or evoked activity between VTA and LC. VTA firing may precede or follow the mPFC firing. Such response pattern may be related to the fact that VTA is a heterogeneous brain region containing dopaminergic, non-dopaminergic and GABA-ergic neurons. We plan to apply juxtacellular labeling technique in combination with immunohistochemical staining procedures in order to more reliably identify the neuronal types in VTA. no notspecified http://www.kyb.tuebingen.mpg.de/ published -27 15017 15421