Neuromodulation

The electrical properties of neurons and their synaptic response can be transiently modulated through the activation of neuromodulatory receptors. These receptors are specific to different neuromodulators, such as dopamine, serotonin and acetylcholine. This neuromodulation is associated with diverse cognitive states, such as arousal, sleep and reward.  Oscillations of neural networks in the brain have long been associated with different brain states, and neuromodulators seem to play a critical role in the induction and modulation of these oscillations – e.g. oscillations cannot be induced in vitro in mammalan brain slice preparations in the absence of neuromodulator receptor agonists. In order to gain a deeper insight into the principles of neuromodulation and its relation to brain function, the lab studies the effect of neuromodulation on microcircuit dynamics.  We investigate  endogenous neuromodulation with specific emphasis on the dopaminergic system. Within an EU-funded consortium (DDPDGENES) consisting of five other labs located in Spain, England and Sweden we furthermore collaborate to map the diversity of the dopamine cells in the brain stem across development and aging. With this study we aim to investigate the functional sub-division of the dopaminergic system.  Exogenous neuromodulation is explored through the effects of commonly used spices on neural activity.

Approach

Characterizing the dopaminergic system in development and aging

Within an EU-funded consortium, DDPDGENES, we aim to map the functional subtypes of dopaminergic (DA) neurons in the substantia nigra, pars compacta (SNc) across development and aging in both rodent and human.  The properties of the mapped  DA subtypes will be compared to those of DA neurons derived from both rodent and human stem cells, with the aim to improve the derivation of DA neurons for treatment of Parkinson’s disease.  DA neurons derived from inducible pluripotent stem cells of patients with Parkinson’s disease will also be analysed and compared to their healthy counterparts. The work of the DDPDGENES consortium will shed new light on the development and aging of the DA system and its functional subdivision in both rodent and human, thus providing a better understanding of the rodent as a model system for human disease.  It should also help gain new knowledge on the DA subtypes affected by Parkinson’s disease.

In the rodent, our investigation makes use of two mouse strains: a transgenic line expressing a green fluorescent protein (eGFP) under the rat tyrosine hydroxylase promotor (TH) and a Cre knock-in inserted in the native DA transporter (DAT) 3’ UTR crossed to a red fluorescent protein (tdTomato) reporter mouse. While TH is the rate-limiting enzyme in catecholamine biosynthesis, DAT regulates neurotransmission by taking up DA into the presynaptic terminal.

Taking advantage of the specific fluorescent labelling of DA neurons in both strains, we aim to study these cells during development and aging at the genetic (g-type), electrophysiologic (e-type) and morphologic (m-type) level in the mouse. Combined, these GEM profiles reflect the general characteristics of individual neurons. With these data we hope to classify the DA neurons of the SNc into different well-defined subtypes. The same analysis will be performed on DA neurons from human fetal tissue and DA neurons derived from various types of stem cells.

Spices as exo-neuromodulators

Little is known about the effect of ingested compounds on brain function.  If compounds contained in food reach the blood stream and pass the blood brain barrier they can potentially exert an effect on neural transmission and thus affect brain states. This is termed exogenous neuromodulation. In this project we examine the effect on neural transmission of compounds isolated from spices used in food across the world.

In the first two parts of the study we focus on the neuronal level, investigating the effect of exogenous compounds on neurons recorded from mouse brain slices. We focus on the glutamatergic neurons of neocortex and amygdala due to their key relevance in CNS signaling. First, neurons are subjected to a set of stimuli designed to provide a fingerprint of the electrical properties (the eCode) in the absence and presence of the different agents. Second, we examine the effects of the bioactive compounds on neuromodulation during neural network activity. This involves a slice preparation that serves as a model for ‘epileptic’ seizures, implemented by blocking all GABAa receptors with an increasing concentration of Gabazine (specific GABAa receptor blocker). Neurons are recorded in the ‘epileptic’ slice in the absence and presence of the different bioactive compounds. Though we examine the effect of our spices in an ‘abnormal’ (i.e. seizure) situation, we believe this provides a simple and clear model that reveals the possible effects spices can have on active brain states.

Finally, we examine the neuromodulatory effects of these compounds in relation to behavior in intact, freely moving animals. The problem is addressed with a battery of behavioral tests that allow us to measure different features in awake, performing animals. These tests are performed on wild type adult mice previously gavaged with saline solution (control group) or the bioactive compound solution.