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The Neurobiology of Stress

The prefrontal cortex (PFC) provides top-down regulation of behavior, cognition, and emotion, including spatial working memory. However, these PFC abilities are greatly impaired by exposure to acute or chronic stress. Chronic stress exposure in rats induces atrophy of PFC dendrites and spines that correlates with working memory impairment. As similar PFC grey matter loss appears to occur in mental illness, the mechanisms underlying these changes need to be better understood. Acute stress exposure impairs PFC cognition by activating feedforward cAMP-calcium- Kþ channel signaling, which weakens synaptic in- puts and reduces PFC neuronal firing. Spine loss with chronic stress has been shown to involve calcium- protein kinase C signaling, but it is not known if inhibiting cAMP signaling would similarly prevent the atrophy induced by repeated stress. The current study examined whether inhibiting cAMP signaling through alpha-2A-adrenoceptor stimulation with chronic guanfacine treatment would protect PFC spines and working memory performance during chronic stress exposure. Guanfacine was selected due to 1) its established effects on cAMP signaling at post-synaptic alpha-2A receptors on spines in PFC, and 2) its increasing clinical use for the treatment of pediatric stress disorders. Daily guanfacine treatment compared to vehicle control was found to prevent dendritic spine loss in layer II/III pyramidal neurons of prelimbic PFC in rats exposed to chronic restraint stress. Guanfacine also protected working memory performance; cognitive performance correlated with dendritic spine density. These findings suggest that chronic guanfacine use may have clinical utility by protecting PFC gray matter from the detrimental effects of stress.
The highly evolved prefrontal cortex (PFC) generates the mental representations needed to provide top-down regulation of behavior, thought and emotion (Arnsten, 2009a). These abilities are often tested in working memory tasks where representations of goals must be held “in mind” and used to guide choice of action. Understanding these PFC mechanisms has particular clinical sig- nificance, as deficits in PFC structure and function are common in mental illness. For example, patients with schizophrenia perform- ing a working memory task show reduced activity in the dlPFC that correlates with symptoms of thought disorder (Perlstein et al., 2001). The onset of schizophrenia is accompanied by waves of gray matter loss in PFC (Cannon et al., 2014), and reduced PFC gray matter is a distinguishing characteristic of the illness (Cannon et al., 2002). Post-mortem studies of the brains of patients with schizo- phrenia have revealed that neuronal cell bodies are retained, but there is an extensive loss of dendrites and spines from layers III and V PFC pyramidal cells (Selemon and Goldman-Rakic, 1999; Glantz and Lewis, 2000; Black et al., 2004; Glausier and Lewis, 2013). In contrast, cortical areas such as the primary visual cortex show more subtle changes (Selemon and Goldman-Rakic, 1999; Glantz and Lewis, 2000).
tudies of nonhuman primate dorsolateral PFC have shown that layer III pyramidal cells form microcircuits that generate the mental representations of visual space needed for spatial working memory (Goldman-Rakic, 1995; Arnsten, 2013). These networks intercon- nect via glutamatergic stimulation of NMDA receptor synapses on dendritic spines (Wang et al., 2013). Research in rodents has shown that exposure to chronic stress induces a marked loss of layer II-III dendritic spines that correlates with impaired working memory (Hains et al., 2009), emphasizing the importance of these synaptic connections to cognitive function.
Understanding the effects of stress on brain physiology has immediate clinical relevance, as mental illnesses such as schizo- phrenia are precipitated and/or exacerbated by stress exposure (Breier et al., 1991; Mazure, 1995). The PFC is particularly sensitive to stress exposure: acute stress exposure rapidly takes PFC “off- line” through neurochemical actions, while repeated stress expo- sure leads to additional architectural changes (Arnsten, 2009b). Acute, uncontrollable stress has been shown to rapidly impair PFC function in monkeys (Arnsten and Goldman-Rakic, 1998), rodents (Murphy et al., 1996) and humans (Qin et al., 2009). In contrast, acute stress exposure often enhances the functioning of subcortical structures, allowing control of behavior to switch from slow, thoughtful PFC regulation to more rapid, reflexive and habitual responses (reviewed in Arnsten (2009a)). Acute stress rapidly im- pairs PFC function through a cascade of intracellular signaling events (Arnsten, 2009b): high levels of stress-induced catechol- amine release in the PFC engage dopamine D1 and noradrenergic alpha-1 and beta receptors, which activate feedforward cAMP- calcium signaling in spines, which in turn open nearby Kþ chan- nels that weaken NMDAR synaptic connections. This series of events reduces PFC neuronal firing and impairs working memory abilities. The effects of stress exposure can be mimicked by acti- vating calcium-protein kinase C (PKC) (Birnbaum et al., 2004) or cAMP-protein kinase A (PKA) signaling (Taylor et al., 1999; Wang et al., 2007) in the PFC. Conversely, inhibiting cAMP signaling via post-synaptic alpha-2A receptors on PFC spines, strengthens con- nectivity and improves cognition through rapid closure of Kþ channels (Wang et al., 2007).
With repeated stress exposure, the noradrenergic system grows stronger (Nestler and Alreja, 1999; Miner et al., 2006; Fan et al., 2013), while there is dendritic atrophy in PFC. Studies of pyrami- dal cells in layer II/III of rat medial PFC have found that repeated stress exposure produces a circuit-specific retraction of dendrites, and a marked loss of spines that is particularly evident in the distal apical tree (Hains et al., 2009; Seib and Wellman, 2003; Radley et al., 2006, 2008; Shansky et al., 2009). These dendritic and spine changes are associated with impaired attentional set-shifting (Liston et al., 2006), and impairment in working memory (Hains et al., 2009), emphasizing their functional significance. In young rats, dendritic atrophy is reversible if the stress exposure is stopped (Radley et al., 2005; Bloss et al., 2011), suggesting that plasticity remains. Similar architectural changes in PFC have been seen in humans, where brain imaging has revealed that repeated stress is associated with reduced PFC gray matter (Ansell et al., 2012) and weaker PFC connections (Liston et al., 2009).
What is causing spine loss in the PFC with repeated stress exposure? Given the immediate clinical relevance of this question, it is important to uncover the mechanisms that contribute to spine loss, and thus develop informed strategies for treatment. Previous research has shown that inhibiting calcium-PKC signaling rescues spine density and working memory from the effects of repeated stress exposure (Hains et al., 2009). Thus, it is possible that inhi- bition of cAMP signaling via alpha-2A receptor stimulation might also be protective. In vitro studies have shown that the application of alpha-2A-adrenoceptor agonists such as guanfacine enrich spinophilin at the cell surface (Brady et al., 2005) and promote spine growth (Hu et al., 2008; Ren et al., 2011) in cell cultures, suggesting that guanfacine may enhance or protect connections in vivo as well. The current study utilized the chronic restraint stress paradigm previously shown to induce spine loss and cognitive impairment in rats (Hains et al., 2009; Radley et al., 2006), and examined whether chronic treatment with the alpha-2A-adrenoceptor agonist, guan- facine, prior to daily stress would protect PFC cognition and spine density from the detrimental effects of chronic stress exposure.
Exposure to either repeated stress or guanfacine treatment significantly reduced weight gain over the 3 week study (Fig. 2A; significant main effect of stress F(1,20) 1⁄4 5.43, p 1⁄4 0.03; significant main effect of guanfacine F(1,20) 1⁄4 6.153, p 1⁄4 0.022; no significant stress by guanfacine interaction F(1,20) 1⁄4 0.78, p 1⁄4 0.783). The reduction in weight gain with chronic stress exposure is similar to that seen in previous studies of restraint stress in rats (Radley et al., 2006).
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Working with Stress at Trauma Recovery Institute
Trauma Recovery Institute offers unparalleled services and treatment approach through unique individual and group psychotherapy. We specialise in long-term relational trauma recovery, sexual trauma recovery and early childhood trauma recovery. We also offer specialized group psychotherapy for psychotherapists and psychotherapy students, People struggling with addictions and substance abuse, sexual abuse survivors and people looking to function in life at a higher level. Trauma recovery Institute offers a very safe supportive space for deep relational work with highly skilled and experienced psychotherapists accredited with Irish Group Psychotherapy Society (IGPS), which holds the highest accreditation standard in Europe. Trauma Recovery Institute uses a highly structured psychotherapeutic approach called Dynamic Psychosocialsomatic Psychotherapy (DPP).

Dynamic Psychosocialsomatic Psychotherapy (DPP) at Trauma Recovery Institute Dublin

Dynamic Psychosocialsomatic Psychotherapy (DPP) is a highly structured, once to twice weekly-modified psychodynamic treatment based on the psychoanalytic model of object relations. This approach is also informed by the latest in neuroscience, interpersonal neurobiology and attachment theory. As with traditional psychodynamic psychotherapy relationship takes a central role within the treatment and the exploration of internal relational dyads. Our approach differs in that also central to the treatment is the focus on the transference and countertransference, an awareness of shifting bodily states in the present moment and a focus on the client’s external relationships, emotional life and lifestyle.
Dynamic Psychosocialsomatic Psychotherapy (DPP) is an integrative treatment approach for working with complex trauma, borderline personality organization and dissociation. This treatment approach attempts to address the root causes of trauma-based presentations and fragmentation, seeking to help the client heal early experiences of abandonment, neglect, trauma, and attachment loss, that otherwise tend to play out repetitively and cyclically throughout the lifespan in relationship struggles, illness and addictions. Clients enter a highly structured treatment plan, which is created by client and therapist in the contract setting stage. The Treatment plan is contracted for a fixed period of time and at least one individual or group session weekly.
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“Talk therapy alone is not enough to address deep rooted trauma that may be stuck in the body, we need also to engage the body in the therapeutic process and engage ourselves as clients and therapists to a complex interrelational therapeutic dyad, right brain to right brain, limbic system to limbic system in order to address and explore trauma that persists in our bodies as adults and influences our adult relationships, thinking and behaviour.”


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