University Neurobiology Report: Mental Illness and Brain Function

This report delves into the neurobiology of mental illness, addressing key questions related to extinction learning, the gut-brain axis, and specific brain regions involved in fear conditioning and extinction. The report begins by explaining the significance of extinction learning in mental illnesses like PTSD, referencing studies that highlight its disruption in antibiotic-treated and germ-free mice and its potential for behavioral intervention. It then explores the ways the gastrointestinal (GI) system and gut microbiota can influence brain function, emphasizing the gut-brain axis and the role of microbiota in behavior. The report also examines the evidence for the involvement of the basolateral amygdala (BLA) in fear conditioning, the infralimbic (IL) cortex and medial prefrontal cortex (mPFC) in extinction learning, and dendritic spine remodeling in learning, citing relevant research findings to support each point. Overall, the report provides a comprehensive overview of the neurobiological mechanisms underlying mental illness and learning processes.

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NEUROBIOLOGY OF MENTAL ILLNESS
NAME: Yousef Salim
STUDENT NUMBER: C3306295
DATE: 12th April 2020
TEACHER: Dr Lauren

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Question 1:Antibiotic-treated (ABX) and germ-free (GF) mice had disrupted extinction
learning. Explain how extinction learning is relevant to mental illness. [20%]
In classical conditioning experiments, a neutral cue is paired with a stimulus, such that subjects
learn to expect the stimulus from the presence of the cue. This pattern, however, ceases when the
cue is presented, but the stimulus does not follow. The ability to unlearn the relation between the
cue and the stimulus is a phenomenon called extinction learning (VanElzakker et al., 2014).
Extinction learning is diminished in mental diseases such as Post Traumatic Stress Disorder
(PTSD). Extinction learning can be applied in behavioural regulation of PSTD patients and other
anxiety-related mental illness (Treanor, 2011)
According to McGuire et al. (2016), there is a significant deficit in fear extinction learning
among individuals suffering from PSTD. Zuj et al. (2016) also add that fear extinction learning
among the PSTD patients is affected by time. The authors also indicate that the extinction of
conditioned fear among the PSTD people can be learned better early in the day after waking than
later in the day. Extinction learning in the management of mental illness targets the
neurobiological mechanisms as a behavioural intervention (Fucich et al., 2016). Extinction
learning stimulates cognitive flexibility and coping behaviour among the rats, according to the
study conducted by Fucich et al. (2016), where the efficacy of fear extinction got tested as a
potential behavioural intervention.
From the perspective of Graham and Milad (2011), fear extinction learning is significant to the
management and understanding of anxiety related disorders. The authors note that fear extinction
model can be utilized as an experimental tool to enable the understanding of the
psychopathology and detection of biomarkers for anxiety disorders. Graham and Milad (2011),
also indicate that fear extinction model can be used in the future to assess the vulnerability,
response to treatment and to guide therapy. The study concludes that there is a relationship
between the neurocircuitry that underscores fear extinction learning and anxiety disorders as
noted in studies involving healthy people, clinical populations and rodents.
Question 2:Describe some of the ways in which the gastrointestinal (GI) system and GI
microbiota can affect brain function. (Hint: they look at some of these in the Nature paper).
[20%]
According to Lerner et al. (2017),empirical literature review indicates that gut-brain axis entails
multichannel sensing and trafficking pathways aimed at conveying signals to the brain. The
components of the multichannel network include neuranatomy that is composed of the vagal and
spinal afferent neurons. The channel also includes the HPA axis that includes the hypothalamus,
pituitary and adrenaline endocrine systems. The channels also entail the electrolytes that act as
gate keepers of the brain and intestinal barriers. The mutual and harmonious interaction between
these channels are necessary for normal brain functioning.

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According to Clark and Mach (2016), the microbiota in the gut significantly influences the host
behaviour, hence playing a key role in the gut-brain axis. Their research indicates that in murine
models there is significant correlation between the physical and emotional stress and changes in
the composition of microbiota especially during exercise.
The study also associates diet to the gut-brain nexus because the type of diet dictates the
composition of the microbiota within the gut. The research also notes that experiments using
prebiotics and probiotics indicate that microbiota acts like an endocrine organ. This is because of
the ability of the gut microbiota to influence the functionality of intestinal barriers and release of
hormones that affect the brain functionality, hence playing a key role in gut-brain axis. The
hypothesis of the study was to underscore if the changes in the moods of the athletes and the
functionality of their gastrointestinal systems would enable deduction of a relationship between
microbes in the gut and the gut-brain axis.
Question 3:Describe the evidence for the involvement of the basolateral amygdala (BLA) in
fear conditioning. [20%]
Amygdala is an important brain region involved in learning, conditioning, and emotional
regulation. Some studies performed with rodents imply that its basolateral division (BLA) stores
the fear memories. For instance, Gale et al. (2004) demonstrated that lesions in BLA impair
recall of both old and fresh fear memories (Gale et al., 2004). However, other studies suggested
that fear conditioning is possible without operative BLA. This claim was investigated by Poulos
et al. (2009). Their results show that although fear learning can occur in BLA-lesioned mice, it
requires much longer training and decays over time faster in comparison with non-lesioned mice
(Poulos et al, 2009). Thereby BLA seems to be an inevitable component of the network that
creates long-lasting and easily accessible fear memories.
According to Liao et al. (2017) indicates that there is a relationship between astrocyte activity in
the BLA and fear memory. The study was conducted using the pharmacological approach
whereby fluorocitrate inhibited the development of fear memory. The study also revealed that in
mice, fear conditioning effectively downregulated astrocytic Rac1 activity in BLA and increased
structural plasticity of the astrocytes. Further, the study revealed that ablation of Rac1 from
theastrocytes within BLA promoted fear acquisition. On the other hand, overexpression or
constitutive activation of the Rac1 in the astrocytes within BLA enables lessening of the
acquisition of the fear memory.
Furthermore, a review by Sun et al. (2020) indicates that BLA is a key player in the circuits that
process fear in humans and mice. The research indicates that fear learning is a result of
prolonged potentiation of inputs that relay information about the specified conditioned stimulus
to the BLA. The research argues that despite the strong information linking synaptic plasticity in
BLA to fear learning, there is unfortunately no mechanism that has fully underpinned the fear
conditioning process.
Question 4:Describe the evidence for the involvement of the infralimbic (IL) cortex and the

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medial prefrontal cortex (mPFC) on extinction learning. [20%]
Hippocampus, mPFC and BLA form a network involved in fear response (Tovote et al., 2015).
Infralimbic cortex (IL) is a subregion of mPFC with glutaminergic projections to BLA that are
implied in modulation of extinction learning (Bloodgood et al., 2018). Fear extinction essentially
requires creation of a new memory that 'overrides' the old, fearful one. For that the old memory
must be suppressed or inhibited. Bloodgood et al. provide evidence that IL projection to BLA is
required to form this new memory. Glutaminergic projections to BLA inhibit its activity in the
presence of the cue, allowing the new memory to form.
Bloodgood et al. (2018) utilized patch-clamp electrophysiology coupled with retrograde tracing
to enable the examination of changes in the neuronal activity of the IL and prelimbic cortex
projections to both the BLA and nucleus accumbens (NAc) following extinction. The study
revealed that extinction influenced a significant increase in the intrinsic excitability of IL-BLA
projections. The study also selectively inhibited PFC-BLA projection neurons during the
extinction processusing the pathway-specific Designer Receptors Exclusively Activated by
Designer Drugs (DREADD). It was noted that the pathway specific inhibition of PFC-BLA
neurons during theextinction processimpaired the possibility of long-term retrieval of such
memory subsequent extinction retrieval. Thus, BLA-mPFC is significant for the extinction
learning process.
Xiong et al (2019) also note that during the retrieval of positive memory through the activation
of the DG engram cells got impaired by a similar simultaneous inhibition of downstream BLA
engram projections to the DG engram cell projections to the nucleus accumbens (NAc).
However, another group of researchers established that IL activity is not necessary to recall the
extinction memory (Do-Monte et al., 2015). In summary, IL seems to be a key component of
unlearning the fearful response; its role is to form a new, fearless memory.
Question 5:Describe the evidence for the involvement of dendritic spine remodelling in
learning. [20%]
Dendritic spines are small protrusions that are connected with neighbouring axons by synapses.
Learning is mediated by synaptic plasticity that is the modulation of the amount and strength of
synaptic connections between cells. During neuroplasticity, dendritic spines can change both in
number and in shape (Xiong et al., 2019).
Fear conditioning and fear extinction require learning the same pattern: the relation between the
cue and stimulus. Thus, it is likely that this process is realized within the same neural circuit.
Indeed, Lai et al. revealed that pyramidal neurons in the frontal association cortex undergo
dynamic structural changes induced by fear learning and re-learning (Lai et al., 2012).
Specifically, the induction of fear response reduces the number of dendritic spines, whereas the
extinction of fear promotes their formation. Interestingly, the protrusions regrow at the locations
of previously eliminated spines, which implies contextual encoding at the level of a single
cortical cell. Moreover, the authors found a strong correlation between the rate of cellular
remodelling and presence of behavioural reaction.

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According to Bosch et al. (2014), synapses store memory through long lasting modifications in
their structure and chemical composition. The study explains how the spatiotemporal
reorganization of the postsynaptic structures is linked to long-term potentiation at each dendritic
spine. The explanation is a clear indication that there is actual remodelling of dendritic spines
during learning and memory acquisition and storage. Also, Gibson and Oliver (2017) define
dendritic spines as multifunctional integrative units that are diverse and dynamic in nature. The
morphology and the density of the dendritic spines change in a matter of minutes from the
influence of a stimulus that leads to learning and memory formation. As such, the study reveals
that structural plasticity of the dendritic spines is a function of synaptic efficiency, learning and
memory as well as other cognitive processes. To conclude, fear conditioning and fear extinction
induce opposing effects on the dendritic spines - the first eliminates them, whereas the second
establishes new ones through the remodelling process.

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