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Our knowledge about the dopaminergic system is very wide. It includes both a myriad of minor facts as well as many milestone findings. This knowledge is the basis of theories created and the fuel for further research. However, in view of the increasing complexity of the emerging image of the dopaminergic system, we should verify whether some of the facts that have been taken for granted for decades are not too simplistic. As an example, I will present two observations recently made in our laboratory. First, the bursting pattern of firing of some dopaminergic neurons does not appear to be dependent on NMDA receptors. There is a population of dopamine (DA) neurons that, in response to the stimulation of cholinergic receptors, shift to a bursting mode of firing. The slow dynamics of the observed phenomenon suggest that it may be the basis of dopamine-dependent maintenance of the prolonged states of increased motivation of the animal. The second observation shows that DA neurons can dynamically change both the parameters and the direction of response to the arriving stimuli, depending on the general state of the brain. Thus, the assumption that DA neurons react stereotypically, with inhibition or excitation to a certain type of stimuli (e.g., aversive sensory), may be too simplistic. When we are dealing with a neural system with such a heterogeneous structure, we should seek to clarify some of our observations in this diversity, instead of trying to adapt to existing knowledge, which is often limited to a homogeneous, simplified image of the dopaminergic system.
BACKGROUND AND AIMS: Dopaminergic midbrain neurons are able to generate two distinct patterns of electrical activity: tonic and bursting. The latter one is suggested to be essential for phasic dopamine release in target structures. It has been previously found that DA-like neurons change their pattern of activity during sleep, with prominent bursting during REM and tonic firing during nonREM phase. Since urethane anaesthesia is postulated to be a model of cyclic sleep-like alternations of the brain state, we have performed experiments aimed to correlate changes in the firing pattern of midbrain DA neurons with changes of the brain state. METHODS: We have performed extracellular in vivo recordings of midbrain DA neurons activity and simultaneous electrocorticographic monitoring of the brain state in urethane anesthetised Wistar rats. RESULTS: Obtained results showed that the activity pattern of putatively DA neurons in the ventral tegmental area subregions (VTA) and substantia nigra pars compacta (SNc) strongly correlates with the cyclic changes in the brain state. This relationship was opposite to the one observed during natural sleep. Tonic firing pattern was dominating during cortical activation (REM-like state) whereas bursting was observed mainly during cortical deactivation (NonREM-like state). Magnitude of this phenomenon was strongly correlated with the anatomical localisation of the recorded neurons within the VTA subregions (PBP, PIF, PN). CONCLUSIONS: Our results confirm that activity of midbrain DA neurons is correlated with alternating states of the brain and shows opposite correlation to the one observed in freely moving animals. They emphasize that the influence of anaesthetic drugs should be taken under consideration during the experiments on dopaminergic midbrain neurons.
INTRODUCTION: Midbrain dopaminergic (DA) neuronal functioning is related to controlling the animal’s orienting and movement towardssalient and/orrewarding stimuli present in the environment. The firing of DA neurons is controlled by various brain regions; however, the main sensory-related innervation is brought by the ipsilateral superior colliculus (SC). Tract tracing experiments suggest that the SC also projects to the contralateral rostromedial tegmental nucleus (RMTg) – the main inhibitory input to DA neurons. Since the orientation of the animal is a manifestation of the imbalance between the left and right DA systems, it is likely that the above-described circuit might explain the lateralization of the motivational/motor behaviours toward the object located on one side of the animal. AIM(S): The aim of this study is to describe the physiology and anatomy of the SC‑RMTg circuit. METHOD(S): Electrophysiological experiments combined with optogenetics were performed to investigate the circuit. The SC of Sprague‑Dawley rats was bilaterally injected with viral vectors containing Channelrhodopsin-2 (ChR2) and yellow fluorescent protein (eYFP) genes. After ChR2 (blue light‑sensitive cation channel) expression, in vivo electrophysiological recordings were performed. RMTg neurons were recorded using 32-channel silicon probes, while either ipsi- or contralateral SC was optogenetically stimulated with laser blue light (473 nm). After each experiment, expression of eYFP and optical fiber location in the SC, as well as, the location of the silicon probe within the RMTg, was histologically verified. RESULTS: Obtained results revealed that stimulation of the contralateral SC was more efficient in increasing firing of the RMTg neurons, as opposed to ipsilateral SC stimulation. Additionally, ipsilateral SC stimulation was more efficient in inhibiting the firing of the RMTg neurons than contralateral SC stimulation. CONCLUSIONS: Such brain wiring might have strong implications for the lateralisation of motivational/locomotor behaviours.
The in vivo preparation is commonly used to study electrophysiology of brain circuits. Since the whole brain network is preserved, electrical activity of one brain region can be observed while the other region is being manipulated (e.g. stimulated or inhibited) in order to determine and characterise connectivity be‑ tween these regions. The recently discovered tool of optogenetics is useful for controlling neuronal activi‑ ty, characterized by high specificity to neurons as well as high temporal resolution. We used this tool to de‑ termine if neurons located within the nucleus incer‑ tus (NI), a population of brainstem central gray GAB‑ Aergic neurons involved in stress response, have an impact on the electrical activity of midbrain dopami‑ nergic neurons located within the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). To prepare the tested neuronal circuit for optogenetic manipulations, NIs of Sprague Dawley rats were ste‑ reotaxically injected with adenoviral associated vector (AAV2-hSyn-hChR2(H134R)-eYFP) containing genes for Channelrhodopsin-2 (ChR2; a blue light-sensitive cation channel) and enhanced yellow fluorescent pro‑ tein (eYFP), which are expressed under control of neu‑ ron specific promoter (human synapsin 1). Two weeks after the operation, when ChR2 and eYFP are fully expressed, in vivo electrophysiological experiments were performed on urethane anaesthetised animals. Dopaminergic neurons within the VTA and SNc were recorded, while NI was stimulated using blue laser light (473 nm, 10–20 mW) led to the tissue using fibre optics. After each experiment the expression of eYFP in the NI, optic fibre placement, as well as the localisa‑ tion of recording electrode within the borders of VTA/ SNc were histologically verified. The results revealed that most (59%) of the midbrain dopaminergic neu‑ rons were strongly inhibited by the optogenetic acti‑ vation of the NI. NI-induced inhibition was followed by rebound excitation in the majority (69%) of respon‑ sive neurons. Additionally, numerous eYFP-positive axons originating from the NI were observed within the VTA and SNc. In conclusion, our results show that NI is a source of strong, presumably direct, inhibitory input to the midbrain dopaminergic system. Optoge‑ netic tools can be used to control the activity of neu‑ rons with high temporal and spatial resolution, both in transgenic and wild-type animals.
Infra slow oscillations (ISO) are low frequency (<0.1Hz) fluctuations detected at the various levels of the brain organisation. In the urethane model of sleep at least a few ISOs can be detected in the rat brain: (1) urethane sleep structure – cyclic alternation of brain state between activated and deactivated EEG patterns; (2) rhythmic, neuronal bursting in the the subcortical visual system – e.g., olivary pretectal nuclei (OPN). Our preliminary observation has revealed that, under constant illumination, the pupil size of the anaesthetised rat oscillates with the period in the range of ISO. The present study was aimed to: (1) determine the relationship between the changes in the pupil size and the ISOs observed in the brain; (2) elucidate the neuronal mechanism of observed pupil size changes. The following signals were simultaneously recorded from urethane anaesthetised rats: multisite ECoG, neuronal firing in left and right OPN, video of the left and right eye. Results revealed that changes of the size of the pupils are synchronised with each other and characterized by two dominant ISO frequencies (~0.01Hz and <0.001Hz). A simple mathematical model of iris smooth muscle constriction and relaxation was proposed to verify the hypothesis that observed changes of the size of the pupils are result of the interference of the three ISOs. The model is governed by the linear first order Ordinary Differential Equation that expresses the muscle relaxation and integration of three ISOs. The parameters of the model were fit to the measured area changes using nonlinear least squares algorithm. It is shown that the area changes predicted from the model correlate well with the observed values. Moreover the analysis revealed that taking all three ISOs into account produces significantly better fit of the model to observed data than any one or two signals, which means that observed pupillary oscillations are result of the interference of all three ISOs recorded in the brain.
The mammalian intergeniculate leaflet (IGL) of the thalamus is a neuronal element of the circadian timing system, which receives direct photic input from the retina. The purpose of this study was to analyze responses of rat IGL neurons in vitro to optic tract stimulation and to identify neurotransmitters released from the terminals of retinal ganglion cells in this structure. Following optic tract stimulation, most of the responding IGL cells were excited and only a minority of them were inhibited. Neurons showing the excitatory response were tested in the presence of AP-5, a selective antagonist of NMDA receptors. In most cases the responses were only partially inhibited by the presence of AP-5. Complete disappearance of excitatory responses was achieved by adding CNQX, an AMPA/kainate receptor-selective antagonist, to the standard incubation fluid. Inhibitory responses were blocked or considerably attenuated in the presence of bicuculline, a GABAA receptor antagonist, in the ACSF. This study demonstrated that glutamate is the main neurotransmitter mediating optic tract input to the IGL, acting mainly via non-NMDA ionotropic receptors. It was also shown that NMDA and GABAA receptors are involved in passing photic input to the IGL, albeit to a much lesser extent.
INTRODUCTION: Dopaminergic (DA) neurons in the ventral tegmental area (VTA) are key players in regulating motivation and learning. Such control is mediated by DA innervation of other brain regions, such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC). AIM(S): With use of optogenetics we aimed to delineate if both electrophysiological activity of DA neurons and DA release in target brain structures follow the optogenetic light stimulation protocols. Additionally, our goal was to compare results obtained with these two approaches. METHOD(S): To address these questions we used genetically modified rats expressing Cre recombinase gene under control of tyrosine hydroxylase gene – a marker of catecholaminergic neurons. Rats were stereotaxically injected into the VTA with adenoviral vectors carrying the Cre-dependent genes for channelrhodopsin-2 (ChR2) and yellow fluorescent protein. After proper expression of ChR2 in DA neurons in vivo electrophysiological or electrochemical experiments (single-unit recordings or fast-scan cyclic voltammetry, respectively) combined with optogenetic stimulation of the VTA were conducted. RESULTS: We demonstrated that laser blue light (473 nm, 5–60 Hz) stimulation alters both the activity of ChR2-expressing TH-positive VTA neurons and DA release in target brain regions. We showed that both DA neuronal firing and DA release elevates not linearly with increasing frequencies of light stimulation. High stimulation frequencies (>20 Hz) decreases both fidelity and amplitude of action potentials, preventing further increase in DA release. Finally, we demonstrated differentiation in DA release within the mesocorticolimbic brain subregions, with higher light-evoked DA concentration in the NAc than in the medial PFC. CONCLUSIONS: ChR2 enables selective control of DA neurons’ activity and subsequent DA release in the target brain regions with high spatial but limited temporal resolution. We demonstrated that light-evoked DA release differ in mesolimbic brain regions. FINANCIAL SUPPORT: This work was supported by the Polish National Science Center (Research grants UMO-2013/11/D/NZ4/02371 and UMO-2014/13/B/ NZ4/00146).
The nucleus incertus (NI) is a brainstem structure formed of GABAergic projection neurons. It is located in the dorsal tegmental pons, below the fourth ventri‑ cle. Axons of NI neurons innervate numerous brain re‑ gions, including the septo-hippocampal system. Previ‑ ous studies have shown that the NI is one of the key el‑ ements involved in the induction of hippocampal theta oscillations. More recently, theta oscillations in the lo‑ cal field potential of the NI were described. Neverthe‑ less, the electrophysiological characteristics of NI neu‑ rons and the involvement of the NI in the mechanisms of theta rhythm generation are unclear. Therefore, the aim of our research is to determine the comprehensive classification of NI neurons in relation to hippocampal theta oscillations. We have performed in vivo electro‑ physiology experiments on 12 urethane anaesthetised Sprague Dawley rats. Under this anaesthetic condition one can observe spontaneous cyclical alternations of brain states (activation and slow wave activity; SWA), characterized by the dominance of different EEG waves (theta and delta oscillations, respectively). Neuronal activity was recorded extracellularly using a 32-chan‑nel recording system in combination with acute micro‑ electrode arrays. Theta rhythm and slow wave activity were recorded from stratum lacunosum-moleculare of hippocampal CA1 field. Our results have revealed that electrical activity of NI neurons (n=147) is brain state dependent. Based on the preference to fire in a specific phase of hippocampal theta rhythm, two main groups of NI neurons could be distinguished: theta phaselocked cells (45%, 66/147) and theta phase-independent cells (55%, 81/147). a majority of theta phase-locked NI neurons fired action potentials in bursts occurring at the rising phase of hippocampal theta oscillation (the‑ ta bursting neurons; 68%, 45/66). Firing rate of theta phase-locked neurons was higher during brain activa‑ tion compared to SWA state. Firing of theta phase-in‑ dependent NI neurons was more heterogeneous and included cells with higher firing rates either during theta oscillations or SWA. Using the multi-channel re‑ cording technique, we have shown that the patterns of NI neuronal activity are more complex than previously described. The resulting in-depth electrophysiological characterization of NI neurons help us to better under‑ stand the mechanisms underlying the formation and synchronization of theta oscillations. Funding: NSC, Poland UMO-2014/15/B/NZ4/04896.
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