Postdoctoral researcher, Queensland University of Technology
The contribution of altered brain plasticity to alcoholism and associated emotional deficits.
Long-term alcohol abuse produces brain maladaptations (or “alcohol-related brain impairments”) that lead to the development of anxiety, depression, memory deficits, cognitive decline and in some cases dementia. These emotional and cognitive deficits are believe to play an pivotal role in the maintenance of alcohol dependence by exacerbating the feeling of craving in abstinent alcoholics.
However, the molecular and cellular maladaptations underlying the development of such alcohol-related impairments are poorly understood. The major objective of my research is to identify the signalling mechanisms and brain circuits altered by chronic alcohol consumption that produce emotional deficits.
I have recently developed a novel technique that involve high resolution microscopy combined with 3D-reconstruction to map the neuronal alterations produced by long-term binge-like consumption of alcohol in mice. This work was a published in a highly specialized journal in the field (Belmer et al, 2016, Brain structure and Function) and was subject to an invitation to publish a mini-review (Belmer et al, 2016, Journal of Neurology and Neuromedecine) and a book chapter in an Encyclopaedia (Encyclopaedia of Signaling Molecules, vol2, Springer).
Using this method, I have identified a particular receptor (5-HT1A) as a regulator of alcohol consumption as well as alcohol-related brain damages and emotional deficits. Alcohol abuse profoundly reduces the regeneration of neurons in a brain region called hippocampus, which consequently produces anxiety, depression and memory deficit. I found that a 2-week chronic treatment with drugs that partially activate the receptor 5-HT1A is able to totally prevent the negative effects of 12 weeks of alcohol consumption on neuronal regeneration within the hippocampus. At the same time, these drugs were also able to prevent the rise of anxiety induced by 24h of alcohol withdrawal in dependent animals.
I am now dissecting the circuitry involved in this process by using state-of-the art techniques called optogenetic and/or chemogenetic to specifically control the activity of various neuronal subtypes within this circuit.
I am also working with a pharmaceutical company to develop more effective and more specific drugs to counteract the negative effects of alcohol on brain plasticity, in order to reduce alcohol-related brain damages and emotional deficits, which are key factors in the relapse of abstinent alcoholics.
Abstract: Our laboratory has previously shown that the smoking-cessation agent varenicline, an agonist/partial agonist of α4β2*, α3β4*, α3β2*, α6β2* (* indicates the possibility of additional subunits) and α7 subunits of nicotinic acetylcholine receptors (nAChRs), reduces ethanol consumption in rats only after long-term exposure (12 weeks). As compounds having partial agonistic activity on α3β4* nAChRs were shown to decrease ethanol consumption in rodents, we assessed here the involvement of the β4 subunit in the effect of varenicline in the reduction of short- and long-term binge-like ethanol drinking in mice.We used the well-validated drinking-in-the-dark (DID) paradigm to model chronic binge-like ethanol drinking in β4(-/-) and β4(+/+) littermate mice and compare the effect of intraperitoneal injection of varenicline (2mg/kg) on ethanol intake following short- (4 weeks) or long-term (12 weeks) exposure.Drinking pattern and amounts of ethanol intake were similar in β4(-/-) and β4(+/+) mice. Interestingly, our results showed that varenicline reduces ethanol consumption following short- and long-term ethanol exposure in the DID. Although the effect of varenicline on the reduction of ethanol consumption was slightly more pronounced in β4(-/-) mice than their β4(+/+) littermates no significant differences were observed between genotypes.In mice, varenicline reduces binge-like ethanol consumption both after short- and long-term exposure in the DID and this effect is independent of β4 nAChR subunit.
Pub.: 04 Oct '16, Pinned: 25 Aug '17
Abstract: Serotonin neurons arise from the brainstem raphe nuclei and send their projections throughout the brain to release 5-HT which acts as a modulator of several neuronal populations. Previous electron microscopy studies in rats have morphologically determined the distribution of 5-HT release sites (boutons) in certain brain regions and have shown that 5-HT containing boutons form synaptic contacts that are either symmetric or asymmetric. In addition, 5-HT boutons can form synaptic triads with the pre- and postsynaptic specializations of either symmetrical or asymmetrical synapses. However, due to the labor intensive processing of serial sections required by electron microscopy, little is known about the neurochemical properties or the quantitative distribution of 5-HT triads within whole brain or discrete subregions. Therefore, we used a semi-automated approach that combines immunohistochemistry and high-resolution confocal microscopy to label serotonin transporter (SERT) immunoreactive axons and reconstruct in 3D their distribution within limbic brain regions. We also used antibodies against key pre- (synaptophysin) and postsynaptic components of excitatory (PSD95) or inhibitory (gephyrin) synapses to (1) identify putative 5-HTergic boutons within SERT immunoreactive axons and, (2) quantify their close apposition to neurochemical excitatory or inhibitory synapses. We provide a 5-HTergic axon density map and have determined the ratio of synaptic triads consisting of a 5-HT bouton in close proximity to either neurochemical excitatory or inhibitory synapses within different limbic brain areas. The ability to model and map changes in 5-HTergic axonal density and the formation of triadic connectivity within whole brain regions using this rapid and quantitative approach offers new possibilities for studying neuroplastic changes in the 5-HTergic pathway.
Pub.: 04 Aug '16, Pinned: 25 Aug '17