Several neurobiological systems are
involved in the regulation of stress responses, specifically endocrine and
neurotransmitter pathways and networks of brain regions that regulate fear
behavior at conscious and unconscious levels. Pathological changes occur in
patients who develop post traumatic stress disorder that were believed to occur
as a consequence of a traumatic experience, downstream from an exposure.

However, these abnormalities in patients with PTSD may represent a pre-existing,
acquired upstream pathology triggered by trauma exposure. Although biological,
psychological and social ramifications of PTSD have been established and
investigated, there is still much more to understand about the underlying
biology of the disorder, specifically brain circuitry and neurochemistry.

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            The central
brain regions that are part of the neural circuitry that mediate stress and are
significantly altered in patients with PTSD are the amygdala, hippocampus, and
medial prefrontal cortex. The hippocampus, responsible for memory functions,
shows the most significant neurological impact from trauma. Patients with PTSD
have reduced hippocampal volume, making it extremely difficult for them to
distinguish between past and present memories or experiences and the ability to
correctly interpret environmental contexts. Furthermore, severe emotional
trauma can create detrimental changes in the ventromedial prefrontal cortex,
which is responsible for regulating emotional responses that are triggered by the
amygdala. There is a decrease in volume and function of the prefrontal cortex
in patients with PTSD. This inhibits ability to regulate negative emotions,
like fear that commonly occurs in patients triggered by specific stimuli. This
is why common symptoms of those suffering from post traumatic stress exhibit
anxiety, fear, and extreme stress responses, even when confronted with stimuli
not directly connected to their past experiences. The third region, the
amygdala, shows an increase in activity in those with PTSD. The amygdala region
processes emotions and is highly linked to fear responses. Patients with PTSD
exhibit hyperactivity in the amygdala in response to stimuli. This increases
panic, anxiety, and stress when patients hear sounds or narratives or are shown
images that relate to their traumatic past. Neuroanatomic features cause
reduced volume and activity in the hippocampus of PTSD patients alters stress
responses and extinction. The amygdala shows increased activity, which promotes
hypervigilance and impairs discrimination of threat. The cortex in patients
with PTSD show reduced volume, reduced anterior cingulate volume, and decreased
medial prefrontal activation which leads to dysregulation of executive
functions and impaired extinction of fear responses.

endocrine and neurotransmitter pathways are neurobiological systems that
regulate stress responses. Patients with PTSD show abnormal regulation of
thyroid hormones and cortisol. The hypothalamic-pituitary-adrenal axis is the
core manager of the neuroendocrine stress response systems. When exposed to
stress, corticotropin-releasing hormone (CRH) is secreted from the neurons in
the hypothalamic paraventricular nucleus (PVN) into the hypothalamo-hypophyseal
portal circulation that stimulates the production and release of
adrenocorticoptropin (ACTH) from the anterior pituitary. Adrenocorticoptropin
in turn causes the release of glucocorticoids from the adrenal cortex that
regulates metabolism and immune/brain function and ultimately manages stressors.

The hypothalamic-pituitary-adrenal axis in patients with PTSD shows
hypocortolism due to increased negative feedback sensitivity of the HPA axis,
caused by increased glucocorticoid receptor binding. Additionally, increased
and sustained levels of CRH concentrations are found in the cerebrospinal fluid
of PTSD patients. Dysregulation of the HPA axis and reduced hippocampal volume
are fundamental features of PTSD. The hypothalamic-pituitary-thyroid axis (HPT)
is the secondary neuroendocrine feature present in patients with PTSD that
regulates blood level of thyroid hormones. Trauma triggers abnormalities in
thyroid hormones; more specifically it increases level of tri-iodothyronine
(T3) and thyroxine (T4). In patients with stress-related syndromes, there was a
disproportionate level of T3 to T4, suggesting that over time trauma will
eventually cause T4 levels to terminate. This abnormal T3:T4 ratio ultimately
causes an increase in subjective anxiety in patients with PTSD.

features including catecholamines, serotonin, amino acids, and peptides are all
neurobiological features of those with post-traumatic stress disorder that
present abnormal regulation. Catecholamine neurotransmitters like
norepinephrine and dopamine are present in high levels in patients with PTSD.

This interferes with fear conditioning by the mesolimbic system and increases
arousal, encoding or fear memories, and startle response. Increased levels of
dopamine and norepinephrine also increase blood pressure, response to memories,
and heart rate. Serotonin (5HT) is a neurotransmitter produced by tryptophan
that affects stress responses depending on the stressor intensity, receptor
type, and region of the brain. Serotonin neurons located on the dorsal raphe
are responsible for mediating anxiogenic effects through the 5HT2 receptors
in the amygdala and hippocampus. The 5HT neurons from the median raphé are
believed to mediate anxiolytic effects through 5HT1A receptors. PTSD
patients with decreased levels of serotonin in their dorsal raphé disturb the
dynamic between the hippocampus and the amygdala. Furthermore, decreased
concentrations of serotonin in the median raphé compromises anxiolytic effects
and increases vigilance, startle, impulsivity, and memory intrusions. As far as
amino acid factors, GABA is the central inhibitory neurotransmitter of the
brain that diminishes behavioral and physiological responses to stressors by
inhibiting CRH/NE circuits that are responsible for mediating stress and fear
response. GABAA receptors increase the inhibitory effects of GABA,
that with immense stress, causes alterations of the GABAA /benzodiazepine
receptor complex. Patients with PTSD will present decreased peripheral
benzodiazepine binding sites. Decreased GABA activity will ultimately compromise
anxiolytic effects. Glutamate is another amino acid and primary excitatory
neurotransmitter that binds to N-methyl D-aspartate (NMDA) receptors that is
involved in the synaptic plasticity, learning, and memory. Increased levels of
glutamate will lead to derealization and dissociation in patients with immense
trauma. Lastly, peptide neurotransmitters, specifically neuropeptide Y,
regulate anxiety and stress. Decreased plasma neuropeptide Y concentrations
upregulates response to stress by leaving corticotropin-releasing hormone and
norepinephrine unopposed. PTSD patients also show increased levels of CSF
beta-endorphin levels, which increases activation of the endogenous opioid
system that is responsible for symptoms like numbing, dissociation, and stress-induced
analgesia in PTSD patients.

binding protein 5 (FKBP5) is a co-chaperone of the glucocorticoid receptor
(GR), and is highly associated with stress reactivity and post-traumatic stress
disorder risk. Hypothalamus-pituitary-adrenal-axis regulation is also a
prominent factor in patients with stress-related disorders like PTSD. Release
of glucocorticoids aids flight or flight responses, and binding of cortisol to
the glucocorticoid receptor is essential to terminate the stress reaction through
negative feedback. This shows that glucocorticoid receptor function is key for
proper stress response regulation. FKBP5 binding to GR is key in modulating GR
sensitivity and reduces cortisol-binding capacity. PTSD patients present
increased cortisol release, which leads to more FKBP5 gene expression and a
reduction in GR sensitivity. Glucocorticoid signaling influences risk of PTSD,
memory, and extinction, with genetic variability of FKBP5 influencing PTSD
vulnerability. FKBP5 genotype is associated with peritraumatic dissociation,
and proves to be a strong risk factor for PTSD development and risk.