Abstract: in clinical populations and is common among

Abstract:

Risky decision
making has significant harmful outcomes in clinical populations and is common
among patients with neuropsychiatric disorders and serious mental illness, for
example schizophrenia. Information transfer between brain regions facilitates
decision making about risks and rewards however, there is a paucity of research
in this area. Employing a task that models risky decision making in rats and
manipulating the transfer of information between two key brain regions, the nucleus accumbens
(NAc) and basolateral amygdala (BLA) which are known to be involved in guiding decisions, will
further our understanding of the neural basis of risky decision making. This is
an important step to further neuropsychiatric research that can inform
treatment options and optimize behaviours.

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Background

In schizophrenics,
irregular tissue organization and volume in the right amygdala and left nucleus
accumbens causes structural and functional abnormalities resulting in abnormal
processing of information (Tomasino et al., 2011; De Rossi et al., 2016).
Schizophrenia research suggests that protuberances within the mesocorticolimbic
system may lead to dysregulation, which inhibits dopamenergic modulation of
processing emotionally salient information (Laviolette, 2007).

 

The nucleus accumbens
(NAc) and basolateral amygdala (BLA) have been identified as key brain regions within
cortico-limbic circuitry for guiding decision making in both humans and animals;
however, reliance on
interpreting functions of different brain regions in isolation lacks external
validity. Determining the way these regions interact to guide behaviour is
essential to understanding what drives risky or safe decisions and ultimately
behaviours. Furthermore, most preclinical studies employ assays to assess
risk/reward decision making using internally generated representations of
outcome contingencies, which are used to guide advantageous  choice. This is problematic because real-life
decisions are often influenced by external stimuli that inform about the
likelihoods of obtaining favourable outcomes. I propose to use a novel assay
colloquially termed the “Blackjack” task that models situations where external
stimuli indicate probabilities (Floresco et al., 2017). Ipsilateral
disconnection of the BLA and NAc, in a rat model, will allow for the
exploration of how information transfer, between these regions, facilitates
decision making about risks and rewards in an externally cued environment.

 

Laboratory
studies designed to assess human ability to make appropriate risk/reward
decisions with functional imaging studies have provided indirect evidence showing
these regions do interact to facilitate decision making about probabilistic
rewards. When choosing high-risk, compared with low-risk gambles, the anterior
cingulate and NAc are functionally connected (Cohen et al., 2005) and
functional connectivity can be observed between the cingulate and amygdala
while anticipating reward outcomes (Marsh et al., 2007).

 

Research
studies have constructed several tasks to investigate the neural basis of
risk/reward decision making in animals. Some are designed to mirror the Iowa
gambling task (Bechara et al., 1999). Other studies have introduced probabilistic
discounting tasks, whereby rats are presented the choice between smaller,
certain rewards, and larger rewards, with the odds of obtaining a larger reward
changing systematically over a session (Stopper et al. 2012).  These tasks have been criticized as not being
representative of “real-life” risk/reward decisions. They are guided by
internally-generated value representations instead of external cues to inform
animals of the likelihood of obtaining certain rewards and therefore do not
mimic “real-life”.

 

These studies, which
used a variety of different behavioural tasks, have established that various
aspects of risk/reward decision making are mediated by neural circuits linking
different regions of the prefrontal cortex, orbitofrontal cortex, nucleus
accumbens and the basolateral amygdala (Larkin et al., 2016). Furthering these
findings about how subcortical circuits mediate risk-based decision making is
important, as it provides insight into the pathophysiology underlying abnormal
decision making.

 

Research has
identified the influence that the basolateral amygdala has in biasing choice
towards larger, uncertain rewards via interactions with the nucleus accumbens. Bilateral
inactivation of either region resulted in a reduced preference of larger
uncertain rewards (Ghods-Sharifi et al. 2009). Asymmetrical disconnection and
inactivation of the BLA and NAc (St Onge et al. 2012) had the same finding. The
roles of both the basolateral amygdala and the nucleus accumbens have been
explored in isolation from one another. The basolateral amygdala reduces the
preference for larger uncertain rewards and the nucleus accumbens supresses random
choice patterns. (Ghods-Sharifi et al., 2009; Floresco et al., 2017). It reamains unclear whether various nodes within the
cortico-amygdalar-striatal circuitry communicate and influence choice and
decisions differently under conditions with external cues versus internally
generated infrormation.

 

To explore this
issue, I propose to use a task involving choice between small/certain and
large/risky rewards. The focus will be on how the BLA-NAc circuitry contributes
to decision making in conditions involving external cues. Previous studies
suggest that the NAc shell is responsible for suppressing irrelevant or
non-rewarded behaviours while the BLA mediates judgements surrounding the
relative value associated with various courses of action (Floresco, 2015;
Ghods-Sharifi et al., 2009).

 

The use of
external cues to guide decisions is essential for adaptive behaviour. Deficits
in such behaviour are associated with a range of neuropsychiatric disorders
which may be in part due to ineffective or absent subcortical circuitry.
Results will contribute to a broader understanding of the underlying
pathophysiology present in neuropsychiatric disorders and the role of the
BLA-NAc pathway.

 

Materials
and Methods

Animals

The experiment will utilize Male Long-Evan rats.
At arrival animals will be group-housed with four animals per cage and given a
week with free food to acclimate. Five days before the intended start date for
behavioural training animals will be food restricted to 16 g per day.

 

Apparatus

Behavioural testing will occur in sound
attenuated operant chambers. The boxes will be ventilated with a fan doubling
as a mechanism to mask external noise. Each chamber will have two retractable
levers, a food receptacle and house light. The retractable levers will be
fitted on either side of the food receptacle.

 

Initial Lever
Press Training Behaviours

Prior to training on the targeted task, animals will
undergo a pre-training regimen consisting of basic lever pressing, retractable
lever training and reward magnitude discrimination training. Before
beginning basic lever pressing each rodent received sugar pellet’s in their
home cage to reduce neophobia. Training will start with lever-press training
under a fixed-ratio-1 (FR1) schedule. During the sessions the house-light will
be illuminated and one lever inserted into the chamber for 30 minutes or until
60 lever presses are made, whichever occurs first. On the following day(s),
rats will be required to press the opposite lever until achieving criterion.

 

Retractable
lever training will begin after completion of basic lever training. Sessions will
consist of 90 trials and begin with both levers retracted and the house-light
off. Every 40 seconds a trial will begin with the illumination of the house
light and the insertion of one of the two levers. If the rat responds within 10
s the lever retracts and a single pellet should be delivered via the food
receptacle with 50% probability. Rats will be trained for approximately 3-6 d
to a criterion of 80 or more successful trials (i.e.