Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition resulting from direct or indirect exposure to serious trauma (death, threatened death, actual or threatened injury, or sexual violence) and involving intrusive reexperiencing of the traumatic event in the form of unwanted memories, nightmares, flashbacks, emotional and physical distress after exposure to traumatic reminders, persistent avoidance symptoms to trauma-related stimuli, negative alterations of cognitions and mood (dissociative amnesia, negative beliefs about oneself, negative emotional state like fear, horror, guilt and inability of experiencing positive emotions), as well as marked alterations of arousal and reactivity related to the traumatic event (irritability, anger, aggression, self-destructive behavior) [1]. The lifetime prevalence of PTSD in the general population according to the Diagnostic Statistical Manual (DSM)-5 criteria is around 8% with women scoring higher than men [2], whereas the prevalence of the disorder among high-risk groups, like war-veterans, may be four times higher [3]. The risk for PTSD increases with the number of traumatic experiences [4], whereas more than 80% of PTSD patients present one or more comorbidities like depression, substance use, and physical health issues which lead to debilitating outcomes [5,6] as well as increased mortality rates [7], rendering, hence, the understanding and treatment of the disease a complex crossroads for the clinician. Multiple studies have shown that trauma-related disorders are associated with the dysfunctioning of numerous biological systems, and that PTSD symptom severity exerts a cumulative effect on premature aging of the immune system and telomere length [8].

Human functional imaging studies have identified an increased connectivity between the ventromedial prefrontal cortex (vmPFC), locus coeruleus (LC), hypothalamus, hippocampus, basolateral amygdala (BLA), and bed nucleus of the stria terminalis (BNST) in PTSD patients, while more subcortical areas like the periaqueductal gray area (PAG) and central amygdala (CeA) gradually become involved when the severity of a threatening stimulus becomes aggravated [9,10].

Before the last decade, the predominant neurobiological model of PTSD concentrated on the pathway of fear conditioning involving mainly the amygdala system [11]. The preparations of the new DSM-5 broadened the criteria to include further emotionally dysregulated states like anger, guilt, shame, and symptoms of derealization and depersonalization, as well as altered self- and other-related conditions and deficits in social cognitions. Such changes also gave rise to new neurobiological research challenges [12]. The emotional dysregulation in PTSD tends to be viewed as a vulnerability factor relating to genetic and developmental parameters and a response to (a) traumatic event(s) during childhood, adolescence or adulthood [11]. Neuroendocrine and neuroimmune findings in PTSD include lower basal cortisol output, increased glucocorticoid receptor (GR) function, and a proinflammatory response pre-, peri-, and post-trauma [13], whereas early trauma [14] and ongoing threat [15] are associated to similar observations. The endocannabinoid system (e-CB) has also been related to the pathophysiology of stress-related psychiatric disorders as PTSD. It includes the main e-CBs: anandamide (AEA) and 2-arachidonoylglycerol (2-AG) that act on receptors type 1 (CB1) and (CB2). The CB1 receptor is widely expressed in the prefrontal-limbic system [16] and, along with anandamide, it positively modulates fear extinction acting mainly in the hippocampus and basolateral amygdala [17]. N-palmitoylethanolamine (PEA), an endogenous lipid modulator, is considered part of the extended e-CB next to AEA and 2-AG is considered an analgesic, neuroprotective and antioxidant agent, exerting its pharmacological function by stimulating the peroxisome proliferator-activated receptor -α (PPAR-α), a ligand-activated nuclear receptor [18]. Research has shown that PEA levels in blood show strong negative association with PTSD symptom severity in humans [19] and become increased by antidepressants in corticolimbic regions of rats [20]. Furthermore, PEA binding at PPAR-α interacts with the gamma-aminobutyric acidergic (GABAergic) neurosteroid system in the biosynthesis of allopregnanolone (Allo) [18]. Allo is a positive allosteric modulator of GABA action at GABA_A receptors and regulates emotional behavior by exerting anxiolytic, antidepressant, sedative effects. It is produced from progesterone in glutamatergic neurons of the cortex, hippocampus and basolateral amygdala through the double enzymatic action of 5α reductase type I (5 α-RI) and 3 α-hydroxysteroid dehydrogenase(3α-HSD) [18,21]. The decrease of Allo in the cerebrospinal fluid of PTSD patients correlates to the severity of reexperiencing and depressive symptoms of both men and women. Interestingly enough, the block in the biosynthesis of Allo is sex-specific relating to 5 α-RI deficiency in men and to 3 α-HSD deficiency in premenopausal women [22,23]. In animal models of PTSD, including the isolated mouse, corticolimbic downregulation of Allo levels correlates to enhanced contextual fear and impaired fear extinction, implying that this neurosteroid may serve as a useful biomarker and treatment option for PTSD across humans and animals [21].

Different models have tried to explain the psychoneurobiological etiology of stress-related mental disorders and their shaping interaction with trauma(s): The three-hit concept of vulnerability and resilience [24] developed by Daskalakis et al. focuses on the interplay between genetic predisposition, early-life adverse events and later-life environment on the occurrence of psychopathology: According to this testable hypothesis, early mild to moderate stress in animals may contribute to stress inoculation and hypothalamic-pituitary-adrenal (HPA) axis adaptability to later adverse events, whereas more severe early stress may affect, beyond HPA-axis functioning, amygdala activation and processing, fear retention, as well as vulnerability to later-life stressors and stress-related disorders (like PTSD) in adulthood. This model does not follow the linearity of the “classic” cumulative stress model (or stress diathesis model), where additive accumulation of different stressors, that exceed a certain threshold, leads to the development of psychopathology to vulnerable individuals, but offers instead an evolutionary counterpart of the dynamic interchange between genetics (hit-1) and early-life events (hit-2) affecting endocrine function and epigenetic modifications, shaping in turn an evolving phenotype which may adapt and resist (resilience) or succumb to mental disorders (vulnerability) when faced with later life stressors (hit-3).

Social bonds play an important role in mediating psychological and physical well-being [25]. Social isolation (SI) stress constitutes a major risk factor of morbidity and mortality for humans as well as nonhuman social species [26]. Research in animals has shown that SI exerts a burdening effect on animal physiology [27], increasing oxidative stress, proinflammatory cytokines, basal cortisol levels, as well as the occurrence of obesity and type II diabetes, urinary catecholamine levels, thus influencing immunity, inflammation control, and genes regulating glucocorticoid responses in a negative way. If post-weaning SI rearing follows maternal separation (reminding us of the three-hit concept of vulnerability), the metabolic risk is multiplied, and rats exhibit up to a 120% increase of fasting glucose compared to group-housed animals [28]. Other study has shown that prior SI in prairie voles alters concentrations of monoamine neurotransmitters following acute restraint, with isolated animals exhibiting elevated serotonin and dopamine levels in the hypothalamus and potentially decreased levels of serotonin in the frontal cortex [29]. Long-term isolated rats also showed a stronger activation of the sympatho-adrenomedullary system (SAS) when faced with new stressors compared to rats chronically exposed to long-term crowded conditions [30]. Neonatal isolation may also increase social dominance and aggression in rats compared to non-isolated controls, resembling the aggressiveness of people who have experienced early neglect. Research has found that neonatal isolation stress increased the stable fraction of actin, which is glucocorticoid dependent and these altered actin dynamics at the spines in the juvenile mPFC may explain neocortical dysfunction leading to altered social behavior later in life [31]. Moreover, in another study, the SI of adolescent mice rendered them unable to forget aversive memories when tested one month after the original event and fear memory retention was explained by the increase of brain-derived neurotrophic factor (BDNF) in the hippocampus [32].

Last but not least, SI is considered a valid animal model of PTSD in the sense that socially isolated animals present symptoms that resemble the human form (face validity) of the disorder like anxiety behavior, contextual fear responses, impaired fear extinction, cognitive alterations, aggressiveness, and neuroendocrine changes [33]. These disturbances are attributed to the corticolimbic downregulation of allopregnanolone (Allo), which normally exerts fast allosteric modulation of the action of GABA at the GABA_A receptors, as mentioned before [21].

In humans, the stress of SI refers to the subjectively perceived feeling of isolation or “loneliness” which does not always coincide with objective social isolation or social support. Neurobiological studies are fewer for obvious reasons, involving more peripheral biological variables: Loneliness has been correlated to a variety of medical conditions, like elevated blood pressure, increased HPA activity, metabolic syndrome, as well as Alzheimer’s disease progression [34]. The upregulation of proinflammatory cytokines during acute stress has, moreover, been observed among the lonelier participants of a study involving healthy adults and breast cancer survivors, implying immune system dysregulation [35]. Loneliness may also predict subsequent depressive symptomatology that cannot be attributed to other parameters [34]. Solitary confinement or disciplinary isolation is a penal tool used in the prison system of the U.S. and other countries against the most violent of the inmates. Segregated individuals display higher levels of mental distress compared to the rest of the general prisoner population and manifest a wide range of psychiatric symptoms ranging from anxiety, panic attacks, and depression, to psychotic symptoms, self-mutilation, or even suicide. Another part of isolated inmates become even more violent after this punitive measure. These detrimental effects of disciplinary segregation have led in the U.S. to calls for the reform of solitary confinement, especially for juvenile offenders, given the irreversible damage that can be caused on their still developing brains [36]. A lack of social support is considered a major risk factor for PTSD following traumatic events [37], while the presence of social support seems to influence symptom severity and recovery [38]. PTSD patients may not make use of social support in order to protect others from distress, thinking that others will not understand or for fear that they will undermine their own self-image [39]. Withdrawal and real or expected negative responses from others relating to early experiences of bullying victimization may cultivate a vicious circle of shame and loneliness in these patients [40]. In addition, the neurobiology of social support is still poorly understood [11].

Given the referred interchange between SI stress and PTSD and in the absence of a systematic review, we wanted to illuminate in this paper the neurobiological trajectories between the two entities and the degree to which the interaction with SI aggravates the (neuro)biological progression of PTSD.