have reductions in the body of the cc, the body and genu of the cc, and only the genu of the cc. reductions of fa have also been reported in the anterior limb of the internal capsule (alic) and superior longitudinal fasciculus. functional neuroimaging studies of resting state activity have utilized a number of indicators of resting state activity, including regional homogeneity (reho), amplitude of low frequency fluctuations (alff), fractional amplitude of low frequency fluctuations (falff), arterial spin labeling (asl), and positron emission tomography measures of regional cerebral blood flow or metabolism. studies using alff and falff have reported elevations in acc activity, with the former primarily reporting more ventral findings, and the latter more dorsal findings. a conjunction analysis of alff and cbf studies converged on the left insula, with previously untreated people having increased insula activity. elevated caudate cbf was also reported a meta analysis combining multiple indicators of resting activity reported elevated anterior cingulate, striatal, and thalamic activity and reduced left insula, post-central gyrus and fusiform gyrus activity. an activation likelihood estimate (ale) meta analysis of pet/spect resting state studies reported reduced activity in the left insula, pregenual and dorsal anterior cingulate cortex and elevated activity in the thalamus, caudate, anterior hippocampus and amygdala. compared to the ale meta analysis of pet/spect studies, a study using multi-kernel density analysis reported hyperactivity only in the pulvinar nuclei of the thalamus. brain regions research on the brains of people with mdd usually shows disturbed patterns of interaction between multiple parts of the brain. several areas of the brain are implicated in studies seeking to more fully understand the biology of depression: subgenual cingulate studies have shown that brodmann area 25, also known as subgenual cingulate, is metabolically overactive in treatment-resistant depression. this region is extremely rich in serotonin transporters and is considered as a governor for a vast network involving areas like hypothalamus and brain stem, which influences changes in appetite and sleep; the amygdala and insula, which affect the mood and anxiety; the hippocampus, which plays an important role in memory formation; and some parts of the frontal cortex responsible for self-esteem. thus disturbances in this area or a smaller than normal size of this area contributes to depression. deep brain stimulation has been targeted to this region in order to reduce its activity in people with treatment resistant depression.: 576–578 prefrontal cortex one review reported hypoactivity in the prefrontal cortex of those with depression compared to controls. the prefrontal cortex is involved in emotional processing and regulation, and dysfunction of this process may be involved in the etiology of depression. one study on antidepressant treatment found an increase in pfc activity in response to administration of antidepressants. one meta analysis published in 2012 found that areas of the prefrontal cortex were hypoactive in response to negative stimuli in people with mdd. one study suggested that areas of the prefrontal cortex are part of a network of regions including dorsal and pregenual cingulate, bilateral middle frontal gyrus, insula and superior temporal gyrus that appear to be hypoactive in people with mdd. however the authors cautioned that the exclusion criteria, lack of consistency and small samples limit results. amygdala the amygdala, a structure involved in emotional processing appears to be hyperactive in those with major depressive disorder. the amygdala in unmedicated depressed persons tended to be smaller than in those that were medicated, however aggregate data shows no difference between depressed and healthy persons. during emotional processing tasks right amygdala is more active than the left, however there is no differences during cognitive tasks, and at rest only the left amygdala appears to be more hyperactive. one study, however, found no difference in amygdala activity during emotional processing tasks. hippocampus atrophy of the hippocampus has been observed during depression, consistent with animal models of stress and neurogenesis. stress can cause depression and depression-like symptoms through monoaminergic changes in several key brain regions as well as suppression in hippocampal neurogenesis. this leads to alteration in emotion and cognition related brain regions as well as hpa axis dysfunction. through the dysfunction, the effects of stress can be exacerbated including its effects on 5-ht. furthermore, some of these effects are reversed by antidepressant action, which may act by increasing hippocampal neurogenesis. this leads to a restoration in hpa activity and stress reactivity, thus restoring the deleterious effects induced by stress on 5-ht. the hypothalamic-pituitary-adrenal axis is a chain of endocrine structures that are activated during the body's response to stressors of various sorts. the hpa axis involves three structure, the hypothalamus which release crh that stimulates the pituitary gland to release acth which stimulates the adrenal glands to release cortisol. cortisol has a negative feedback effect on the pituitary gland and hypothalamus. in people with mdd this often shows increased activation in depressed people, but the mechanism behind this is not yet known. increased basal cortisol levels and abnormal response to dexamethasone challenges have been observed in people with mdd. early life stress has been hypothesized as a potential cause of hpa dysfunction. hpa axis regulation may be examined through a dexamethasone suppression tests, which tests the feedback mechanisms. non-suppression of dexamethasone is a common finding in depression, but is not consistent enough to be used as a diagnostic tool. hpa axis changes may be responsible for some of the changes such as decreased bone mineral density and increased weight found in people with mdd. one drug, ketoconazole, currently under development has shown promise in treating mdd. hippocampal neurogenesis reduced hippocampal neurogenesis leads to a reduction in hippocampal volume. a genetically smaller hippocampus has been linked to a reduced ability to process psychological trauma and external stress, and subsequent predisposition to psychological illness. depression without familial risk or childhood trauma has been linked to a normal hippocampal volume but localised dysfunction. animal models a number of animal models exist for depression, but they are limited in that depression involves primarily subjective emotional changes. however, some of these changes are reflected in physiology and behavior, the latter of which is the target of many animal models. these models are generally assessed according to four facets of validity; the reflection of the core symptoms in the model; the predictive validity of the model; the validity of the model with regard to human characteristics of etiology; and the biological plausibility. different models for inducing depressive behaviors have been utilized; neuroanatomical manipulations such as olfactory bulbectomy or circuit specific manipulations with optogenetics; genetic models such as 5-ht1a knockout or selectively bred animals; models involving environmental manipulation associated with depression in humans, including chronic mild stress, early life stress and learned helplessness. the validity of these models in producing depressive behaviors may be assessed with a number of behavioral tests. anhedonia and motivational deficits may, for example, be assessed via examining an animal's level of engagement with rewarding stimuli such as sucrose or intracranial self-stimulation. anxious and irritable symptoms may be assessed with exploratory behavior in the presence of a stressful or novelty environment, such as the open field test, novelty suppressed feeding, or the elevated plus-maze. fatigue, psychomotor poverty, and agitation may be assessed with locomotor activity, grooming activity, and open field tests. animal models possess a number of limitations due to the nature of depression. some core symptoms of depression, such as rumination, low self-esteem, guilt, and depressed mood cannot be assessed in animals as they require subjective reporting. from an evolutionary standpoint, the behavior correlates of defeats of loss are thought to be an adaptive response to prevent further loss. therefore, attempts to model depression that seeks to induce defeat or despair may actually reflect adaption and not disease. furthermore, while depression and anxiety are frequently comorbid, dissociation of the two in animal models is difficult to achieve. pharmacological assessment of validity is frequently disconnected from clinical pharmacotherapeutics in that most screening tests assess acute effects, while antidepressants normally take a few weeks to work in humans. neurocircuits regions involved in reward are common targets of manipulation in animal models of depression, including the nucleus accumbens (nac), ventral tegmental area (vta), ventral pallidum (vp), lateral habenula (lhb) and medial prefrontal cortex (mpfc). tentative fmri studies in humans demonstrate elevated lhb activity in depression. the lateral habenula projects to the rmtg to drive inhibition of dopamine neurons in the vta during omission of reward. in animal models of depression, elevated activity has been reported in lhb neurons that project to the ventral tegmental area (ostensibly reducing dopamine release). the lhb also projects to aversion reactive mpfc neurons, which may provide an indirect mechanism for producing depressive behaviors. learned helplessness induced potentiation of lhb synapses are reversed by antidepressant treatment, providing predictive validity. a number of inputs to the lhb have been implicated in producing depressive behaviors. silencing gabaergic projections from the nac to the lhb reduces conditioned place preference induced in social aggression, and activation of these terminals induces cpp. ventral pallidum firing is also elevated by stress induced depression, an effect that is pharmacologically valid, and silencing of these neurons alleviates behavioral correlates of depression. tentative in vivo evidence from people with mdd suggests abnormalities in dopamine signalling. this led to early studies investigating vta activity and manipulations in animal models of depression. massive destruction of vta neurons enhances depressive behaviors, while vta neurons reduce firing in response to chronic stress. however, more recent specific manipulations of the vta produce varying results, with the specific animal model, duration of vta manipulation, method of vta manipulation, and subregion of vta manipulation all potentially leading to differential outcomes. stress and social defeat induced depressive symptoms, including anhedonia, are associated with potentiation of excitatory inputs to dopamine d2 receptor-expressing medium spiny neurons (d2-msns) and depression of excitatory inputs to dopamine d1 receptor-expressing medium spiny neurons (d1-msns). optogenetic excitation of d1-msns alleviates depressive symptoms and is rewarding, while the same with d2-msns enhances depressive symptoms. excitation of glutaminergic inputs from the ventral hippocampus reduces social interactions, and enhancing these projections produces susceptibility to stress-induced depression. manipulations of different regions of the mpfc can produce and attenuate depressive behaviors. for example, inhibiting mpfc neurons specifically in the intralimbic cortex attenuates depressive behaviors. the conflicting findings associated with mpfc stimulation, when compared to the relatively specific findings in the infralimbic cortex, suggest that the prelimbic cortex and infralimbic cortex may mediate opposing effects. mpfc projections to the raphe nuclei are largely gabaergic and inhibit the firing of serotonergic neurons. specific activation of these regions reduce immobility in the forced swim test but do not affect open field or forced swim behavior. inhibition of the raphe shifts the behavioral phenotype of uncontrolled stress to a phenotype closer to that of controlled stress. altered neuroplasticity recent studies have called attention to the role of altered neuroplasticity in depression. a review found a convergence of three phenomena: chronic stress reduces synaptic and dendritic plasticity depressed subjects show evidence of impaired neuroplasticity (e.g. shortening and reduced complexity of dendritic trees) anti-depressant medications may enhance neuroplasticity at both a molecular and dendritic level. the conclusion is that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants. blood levels of bdnf in people with mdd increase significantly with antidepressant treatment and correlate with decrease in symptoms. post mortem studies and rat models demonstrate decreased neuronal density in the prefrontal cortex thickness in people with mdd. rat models demonstrate histological changes consistent with mri findings in humans, however studies on neurogenesis in humans are limited. antidepressants appear to reverse the changes in neurogenesis in both animal models and humans. inflammation various reviews have found that general inflammation may play a role in depression. one meta analysis of cytokines in people with mdd found increased levels of pro-inflammatory il-6 and tnf-a levels relative to controls. the first theories came about when it was noticed that interferon therapy caused depression in a large number of people receiving it. meta analysis on cytokine levels in people with mdd have demonstrated increased levels of il-1, il-6, c-reactive protein, but not il-10. increased numbers of t-cells presenting activation markers, levels of neopterin, ifn gamma, stnfr, and il-2 receptors have been observed in depression. various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems, diet, smoking and obesity. cytokines, by manipulating neurotransmitters,