Book of abstracts - British Neuroscience Association

18.03
Finding cells for replacement therapy in Huntington’s disease
Rosser AE, Kelly CM , Allen ND , Zietlow R , Jeyasingham J , Pekarik
V , Dunnett SB
1. Cardiff University School of Biosciences, PO BOX 911, Museum Av,
Cardiff CF10 3US , , 2. Dept Neurology,, University of Wales College
of Medicine, Heath Park, Cardiff CF14 4XN,
The most striking pathology in Huntington’s disease (HD) in the early
to moderate stages is the loss of medium spiny neurons (MSNs) from
the striatum. One treatment strategy is to implant developing MSNs in
an attempt to reconstruct damaged neuronal circuits. To date, the
success of this approach has depended on harvesting cells from the
developing striatum during a specific development window. A small
number of ongoing clinical studies world-wide have demonstrated the
safety of this procedure and have provided preliminary evidence of
efficacy. However, the practical difficulties associated with the
collection of human fetal tissue make it imperative to identify an
alternative source of donor cells.
Stem cells from various sources may provide a renewable source of
donor cells, but functional benefit will depend on neurons differentiating
from such populations being of an MSN phenotype. It is this
requirement that currently presents the greatest challenge for the
clinical application of such cells.
We focus on neural precursor cells isolated from either human fetal
CNS or embryonic stem (ES) cells. We show that differentiation
phenotype is influenced by expansion in vitro and that MSN phenotype
may be retained after limited expansion. We undertook a systematic
Affymetrix analysis of developing striatal neurons in order to identify
factors important for normal MSN differentiation, and are currently
validating significantly up-regulated genes as markers of the MSN
phenotype and for their role in MSN differentiation. Ultimately this
information will be used to make rational manipulations of the culture
conditions to promote MSN differentiation.
18.04
Neural stem cells for the treatment of Parkinsons disease.
Caldwell M
, Henry Wellcome Laboratory for Integrative Neuroscience and
Endocrinology, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY
Neural stem cells can be isolated from the developing and adult brain and
can be expanded in culture with the mitogens epidermal growth factor
(EGF) and fibroblast growth factor (FGF2). However, as they expand in
culture they lose their neurogenic potential and become more gliogenic.
With that in mind these cells would have limited usefulness for the
treatment of neurodegenerative diseases such as Parkinsons Disease
which affects more than one percent of the population over the age of 65.
However, recent studies have shown that overexpression of transcription
factors such as Nurr1 or pitx3 (both important during dopamine neuron
development and maintenance) result in generation of dopamine neurons.
Here we show that overexpression of Pitx3 in neural stem cells results in
larger numbers of dopamine neurons when cocultured with developing
ventral mesencephalon. This has a significant effect on behavioural
recovery in a variety of motor tasks and greater survival of dopamine
neurons in transplants. This could have implications for the treatment of
Parkinsons Disease.
19.01
Neuroanotomical substrates and disorders of frontal-lobe related
cognitive processes
Garavan H
School of Psychology, Trinity College, Dublin 2, Ireland
While there is a consensus that the frontal lobes play a critical role in
regulating behaviour, the particulars of how this is accomplished are
still far from clear. This talk will describe a number of recent studies
from my lab that attempt to describe the neurobiology of regulatory
processes such as inhibitory and attentional control, performance
monitoring and control over automatic behaviours. Our results suggest
that the right PFC, especially right inferior frontal gyrus, is central to
inhibitory control. The anterior cingulate appears to monitor behaviour
and serves a central role in intervening when ongoing behaviour
should be interrupted either to avoid an error or attain a large reward.
Left PFC may have a central role in maintaining task goals and
interactions between it and other regions involved in implementing
control will be described. In addition to understanding the neural
substrates of these functions, we will also describe evidence of their
dysfunction in substance dependent individuals, a group characterised
by impoverished control over behaviour. Drug users show reduced
activity in the anterior cingulate and have a poorer awareness of their
performance failures. In addition, reduced PFC activity associated with
inhibitory control appears to be accompanied by reliance on suboptimal
cerebellar networks. These results suggest that impairments in
cognitive control may be an important element of drug dependence,
either in its maintenance or in increasing risk of relapse.
19.02
Novel Therapeutic Targets for Stress-Related Disorders
Cryan J F
School of Pharmacy, Dept Pharmacology & Therapeutics, University
College Cork
The complex interaction between stress and genetics that leads to the
manifestation of disorders such as depression, anxiety, drug dependence,
cognitive dysfunction and irritable bowel syndrome in certain susceptible
individuals is one of prime interest in neuroscience. This is paralleled with
efforts to develop pharmacological strategies to counteract the deleterious
effects of stress. It is largely thought that an imbalance of the
neurotransmitters GABA and glutamate are responsible at least in part for
the manifestation of many stress-related disorders. Their fast actions are
mediated by ionotropic receptors. In addition, metabotropic receptors
mediate slower modulatory actions of GABA and glutamate on
neurotransmitter release and cell excitability. Of all glutamate receptors, the
role of group III metabotropic glutamate receptors (mGluR4; mGluR6;
mGluR7; mGluR8) and in particular mGluR7 in stress-related disorders is
the least investigated because of the lack of specific tools. Likewise a
definitive role of metabotropic GABAB receptors in such disease states has
remained elusive. In this presentation, recent data highlighting the role of
these two receptors in stress related disorders will be highlighted. The
development of novel pharmacological (allosteric modulators and
antagonists) and genetic tools (knockout, knockin and siRNA-induced
knockdown) for GABAB and mGluR7 has allowed the investigation of their
role in the manifestation of the molecular, neurochemical and behavioural
responses induced by stress; aversive fear learning and drugs of abuse. In
parallel we are investigating the contribution of cortical regions such as the
anterior cingulated cortex and infralimbic cortex to the manifestation of
anxiety and depression-like behaviour.
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