Differential involvement of rat medial prefrontal cortex dopamine receptors in modulation of hypothalamic- pituitary-adrenal axis responses to different stressors

Recent investigations have implicated the medial prefrontal cortex (mPFC) in modulation of subcortical pathways that contribute to the generation of behavioural, autonomic and endocrine responses to stress. However, little is known of the mechanisms involved. One of the key neurotransmitters involved in mPFC function is dopamine, and we therefore aimed, in this investigation, to examine the role of mPFC dopamine in response to stress in Wistar rats. In this regard, we infused dopamine antagonists SCH23390 or sulpiride into the mPFC via retrodialysis. We then examined changes in numbers of cells expressing the c-fos immediate-early gene protein product, Fos, in subcortical neuronal populations associated with regulation of hypothalamic-pituitary-adrenal (HPA) axis stress responses in response to either of two stressors; systemic injection of interleukin-1β, or air puff. The D1 antagonist, SCH23390, and the D2 antagonist, sulpiride, both attenuated expression of Fos in the medial parvocellular hypothalamic paraventricular nucleus (mpPVN) corticotropin-releasing factor cells at the apex of the HPA axis, as well as in most extra-hypothalamic brain regions examined in response to interleukin-1β. By contrast, SCH23390 failed to affect Fos expression in response to air puff in any brain region examined, while sulpiride resulted in an attenuation of the air puff-induced response in only the mpPVN and the bed nucleus of the stria terminalis. These results indicate that the mPFC differentially processes the response to different stressors and that the two types of dopamine receptor may have different roles.

Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress : possible role of the bed nucleus of the stria terminalis

The medial prefrontal cortex (mPFC) has been strongly implicated in control of the paraventricular nucleus of the hypothalamus (PVN) response to stress. Because of the paucity of direct projections from the mPFC to the PVN, we sought to investigate possible brain regions that might act as a relay between the two during psychological stress. Bilateral ibotenic acid lesions of the rat mPFC enhanced the number of Fos-immunoreactive cells seen in the PVN after exposure to the psychological stressor, air puff. Altered neuronal recruitment was seen in only one of the candidate relay populations examined, the ventral bed nucleus of the stria terminalis (vBNST). Furthermore, bilateral ibotenic acid lesions of the BNST caused a significant attenuation of the PVN response to air puff. To better characterize the structural relationships between the mPFC and PVN, retrograde tracing studies were conducted examining Fos expression in cells retrogradely labeled with cholera toxin b subunit (CTb) from the PVN and the BNST. Results obtained were consistent with an important role for both the mPFC and BNST in the mpPVN CRF cell response to air puff. We suggest a set of connections whereby a direct PVN projection from the ipsilateral vBNST is involved in the mpPVN response to air puff and this may, in turn, be modulated by an indirect projection from the mPFC to the BNST.

Medial prefrontal cortex suppression of the hypothalamic–pituitary–adrenal axis response to a physical stressor, systemic delivery of interleukin-1β

Previous studies have shown that the medial prefrontal cortex can suppress the hypothalamic–pituitary–adrenal axis response to stress. However, this effect appears to vary with the type of stressor. Furthermore, the absence of direct projections between the medial prefrontal cortex and corticotropin-releasing factor cells at the apex of the hypothalamic–pituitary–adrenal axis suggest that other brain regions must act as a relay when this inhibitory mechanism is activated. In the present study, we first established that electrolytic lesions involving the prelimbic and infralimbic medial prefrontal cortex increased plasma adrenocorticotropic hormone levels seen in response to a physical stressor, the systemic delivery of interleukin-1β. However, medial prefrontal cortex lesions did not alter plasma adrenocorticotropic hormone levels seen in response to a psychological stressor, noise. To identify brain regions that might mediate the effect of medial prefrontal cortex lesions on hypothalamic–pituitary–adrenal axis responses to systemic interleukin-1β, we next mapped the effects of similar lesions on interleukin-1β-induced Fos expression in regions previously shown to regulate the hypothalamic–pituitary–adrenal axis response to this stressor. It was found that medial prefrontal cortex lesions reduced the number of Fos-positive cells in the ventral aspect of the bed nucleus of the stria terminalis. However, the final experiment, which involved combining retrograde tracing with Fos immunolabelling, revealed that bed nucleus of the stria terminalis-projecting medial prefrontal cortex neurons were largely separate from medial prefrontal cortex neurons recruited by systemic interleukin-1β, an outcome that is difficult to reconcile with a simple medial prefrontal cortex–bed nucleus of the stria terminalis–corticotropin-releasing factor cell control circuit.

Repeated social defeat selectively increases ΔFosB expression and histone H3 acetylation in the infralimbic medial prefrontal cortex

Exposure to social stress has been linked to the development and maintenance of mood-related psychopathology; however, the underlying neurobiological changes remain uncertain. In this study, we examined numbers of ΔFosB-immunoreactive cells in the forebrains of rats subjected to 12 episodes of social defeat. This was achieved using the social conflict model whereby animals are introduced into the home cage of older males (“residents”) trained to attack and defeat all such “intruders”; importantly, controls were treated identically except that the resident was absent. Our results indicated that the only region in which ΔFosB-positive cells were found in significantly higher numbers in intruders than in controls was the infralimbic medial prefrontal cortex (mPFC). This same effect was not apparent using another psychological stressor, noise stress. Cells of the infralimbic mPFC also displayed evidence of chromatin remodeling. We found that exposure to repeated episodes of social defeat increased numbers of cells immunoreactive for histone H3 acetylation, but not for histone H3 phosphoacetylation, in the infralimbic mPFC. Collectively, these findings highlight the importance of the infralimbic mPFC in responding to social stress—a finding that provides insight into the possible neurobiological alterations associated with stress-induced psychiatric illness.

Role of catecholaminergic inputs to the medial prefrontal cortex in local and subcortical expression of Fos after psychological stress

A wide variety of stressors elicit Fos expression in the medial prefrontal cortex (mPFC). No direct attempts, however, have been made to determine the role of the inputs that drive this response. We examined the effects of lesions of mPFC catecholamine terminals on local expression of Fos after exposure to air puff, a stimulus that in the rat acts as an acute psychological stressor. We also examined the effects of these lesions on Fos expression in a variety of subcortical neuronal populations implicated in the control of adrenocortical activation, one classic hallmark of the stress response. Lesions of the mPFC that were restricted to dopaminergic terminals significantly reduced numbers of Fos-immunoreactive (Fos-IR) cells seen in the mPFC after air puff, but had no significant effect on stress-induced Fos expression in the subcortical structures examined. Lesions of the mPFC that affected both dopaminergic and noradrenergic terminals also reduced numbers of Fos-IR cells observed in the mPFC after air puff. Additionally, these lesions resulted in a significant reduction in stress-induced Fos-IR in the ventral bed nucleus of the stria terminalis. These results demonstrate a role for catecholaminergic inputs to the mPFC, in the generation of both local and subcortical responses to psychological stress.

Regulators of mitochondrial complex I activity: a review of literature and evaluation in postmortem prefrontal cortex from patients with bipolar disorder

Phenomenologically, bipolar disorder (BD) is characterized by biphasic increases and decreases in energy. As this is a state-related phenomenon, identifying regulators responsible for this phasic dysregulation has the potential to uncover key elements in the pathophysiology of BD. Given the evidence suggesting mitochondrial complex I dysfunction in BD, we aimed to identify the main regulators of complex I in BD by reviewing the literature and using the published microarray data to examine their gene expression profiles. We also validated protein expression levels of the main complex I regulators by immunohistochemistry. Upon reviewing the literature, we found PARK-7, STAT-3, SIRT-3 and IMP-2 play an important role in regulating complex I activity. Published microarray studies however revealed no significant direction of regulation of STAT-3, SIRT-3, and IMP-2, but a trend towards downregulation of PARK-7 was observed in BD. Immunocontent of DJ-1 (PARK-7-encoded protein) were not elevated in post mortem prefrontal cortex from patients with BD. We also found a trend towards upregulation of DJ-1 expression with age. Our results suggest that DJ-1 is not significantly altered in BD subjects, however further studies are needed to examine DJ-1 expression levels in a cohort of older patients with BD.

Increased levels of SNAP-25 and synaptophysin in the dorsolateral prefrontal cortex in bipolar I disorder

Objective:  In order to identify whether the mechanisms associated with neurotransmitter release are involved in the pathologies of bipolar disorder and schizophrenia, levels of presynaptic [synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin, vesicle-associated membrane protein, dynamin I] and structural (neuronal cell adhesion molecule and alpha-synuclein) neuronal markers were measured in Brodmann's area 9 obtained postmortem from eight subjects with bipolar I disorder (BPDI), 20 with schizophrenia and 20 controls.
Methods:  Determinations of protein levels were carried out using Western blot techniques with specific antibodies. Levels of mRNA were measured using real-time polymerase chain reaction.
Results:  In BPDI, levels of SNAP-25 (p < 0.01) and synaptophysin (p < 0.05) increased. There were no changes in schizophrenia or any other changes in BPDI. Levels of mRNA for SNAP-25 were decreased in BPDI (p < 0.05).
Conclusion:  Changes in SNAP-25 and synaptophysin in BPDI suggest that changes in specific neuronal functions could be linked to the pathology of the disorder.

Low-frequency brain stimulation to the left dorsolateral prefrontal cortex increases the negative impact of social exclusion among those high in personal distress

The dorsolateral prefrontal cortex (DLPFC) is thought to play a key role in the cognitive control of emotion and has therefore, unsurprisingly, been implicated in the regulation of physical pain perception. This brain region may also influence the experience of social pain, which has been shown to activate similar neural networks as seen in response to physical pain. Here, we applied sham or active low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC, previously shown to exert bilateral effects in pain perception, in healthy participants. Following stimulation, participants played the “Cyberball Task”; an online ball-tossing game in which the subject participant is included or excluded. Compared to sham, rTMS did not modulate behavioural response to social exclusion. However, within the active rTMS group only, greater trait personal distress was related to enhanced negative outcomes to social exclusion. These results add further support to the notion that the effect of brain stimulation is not homogenous across individuals, and indicates the need to consider baseline individual differences when assessing response to brain stimulation. This seems particularly relevant in social neuroscience investigations, where trait factors may have a meaningful effect.

Ability of predator odour exposure to elicit conditioned versus sensitised post traumatic stress disorder-like behaviours, and forebrain ΔFosB expression, in rats

At present, exposure of a rodent to the odour of a predator is one of the most common animal models of post traumatic stress disorder (PTSD). Despite this, the model remains incompletely characterized, particularly in regard to within subject assessment of major PTSD-like behaviours. In an attempt to redress this situation, we have extensively characterized the two broad categories of behaviour that are considered to characterize PTSD, that is sensitized behaviours such as social withdrawal and hypervigilance and conditioned behaviours such as avoidance of trauma linked cues. Specifically, we determined the presence and duration of both conditioned and sensitized behaviours, in the same cohort of animals, after three exposures to predator odour. Conditioned fear was assessed on the basis of inhibition of locomotor activity upon return to context 2, 7, 14, 21, and 28 days after the last odour exposure session. To assess the impact on sensitization behaviours, we monitored acoustic startle responses and social interaction behaviour 4, 9, 16, 23, and 30 days after the last exposure session. In addition to examining the behavioural consequences associated with odour exposure, we also determined the key brain regions that were activated using ΔFosB immunohistochemistry. Our results show that the two groups of behaviours thought to characterize PTSD (conditioned and sensitized) do not travel together in the predator odour model, with clear evidence of enduring changes in conditioned fear but little evidence of changes in social interaction or acoustic startle. With regard to associated patterns of activity in the brain, we observed that odour-exposed animals exhibited significantly higher numbers of FosB-positive nuclei in only the medial prefrontal cortex (mPFC), a finding that can be viewed as being consistent with the observed behavioural changes.

Coping with defeat : acute glucocorticoid and forebrain responses to social defeat vary with defeat episode behaviour

Individuals vary in the way in which they cope with stressful situations. It has been suggested that ‘active’ coping behaviour, characterised by aggression and territorial control, is more effective in moderating the stress associated with social defeat than ‘passive’ coping behaviour, as characterised by immobility, decreased reactivity, and low aggression. We used the rodent ‘resident/intruder’ paradigm to determine whether individual differences in coping behaviour modulate the acute adrenocortical response to social defeat. During the 10 min conflict episode, behaviours displayed by the intruder were recorded and subsequently scored. Intruders that engaged in large numbers of fights and/or frequently used physical structures to block the resident's approach (a behaviour referred to as ‘guarding’), displayed smaller corticosterone responses to defeat than other intruders. Corticosterone responses to defeat were unrelated to a measure of coping style preferences (defensive burying test) obtained prior to the defeat encounter. We further chose to investigate the neurobiological basis of this observation by comparing the patterns of defeat-induced neuronal activation in the forebrains of intruders that displayed high versus low numbers of defensive behaviours during the defeat episode. The results of this analysis indicated that ‘low fight’ and ‘low guard’ intruders, i.e. those that achieved a fight or a guard score below the 20th percentile, had significantly higher numbers of Fos-positive neurons in forebrain regions such as the medial prefrontal cortex and the amygdala than did control animals exposed to an empty resident's cage. In summary, the present data suggest that ‘active’ coping behaviour is associated with both a smaller adrenocortical response and a lower level of ‘neural activation’ following social defeat. This outcome differs from that of earlier studies, a difference that we suggest is due to the fact that the present study is the first to assess coping on the basis of behaviour actually displayed during the conflict interaction.