Neuropeptide Y (NPY) and posttraumatic stress disorder (PTSD): A translational update.

Posttraumatic stress disorder (PTSD) is a trauma-evoked syndrome, with variable prevalence within the human population due to individual differences in coping and resiliency. In this review, we discuss evidence supporting the relevance of neuropeptide Y (NPY), a stress regulatory transmitter in PTSD. We consolidate findings from preclinical, clinical, and translational studies of NPY that are of relevance to PTSD with an attempt to provide a current update of this area of research. NPY is abundantly expressed in forebrain limbic and brainstem areas that regulate stress and emotional behaviors. Studies in rodents demonstrate a role for NPY in stress responses, anxiety, fear, and autonomic regulation, all relevant to PTSD symptomology. Genetic studies support an association of NPY polymorphisms with stress coping and affect. Importantly, cerebrospinal fluid (CSF) measurements in combat veterans provide direct evidence of NPY association with PTSD diagnosis and symptomology. In addition, NPY involvement in pain, depression, addiction, and metabolism may be relevant to comorbidities associated with PTSD. Collectively, the literature supports the relevance of NPY to PTSD pathophysiology, although knowledge gaps remain. The NPY system is an attractive target in terms of understanding the physiological basis of PTSD as well as treatment of the disorder.

Divergent effects of repeated restraint versus chronic variable stress on prefrontal cortical immune status after LPS injection.

Previous work from our group has shown that chronic homotypic stress (repeated restraint - RR) increases microglial morphological activation in the prefrontal cortex (PFC), while chronic heterotypic stress (chronic variable stress - CVS) produces no such effect. Therefore, we hypothesized that stressor modality would also determine the susceptibility of the PFC to a subsequent inflammatory stimulus (low dose lipopolysaccharide (LPS)). We found that RR, but not CVS, increased Iba-1 soma size in the PFC after LPS injection, consistent with microglial activation. In contrast, CVS decreased gene expression of proinflammatory cytokines and Iba-1 in the PFC under baseline conditions, which were not further affected by LPS. Thus, RR appears to promote microglial responses to LPS, whereas CVS is largely immunosuppressive. The results suggest that neuroimmune changes caused by CVS may to some extent protect the PFC from subsequent inflammatory stimuli. These data suggest that modality and/or intensity of stressful experiences will be a major determinant of central inflammation and its effect on prefrontal cortex-mediated functions.

Neuropeptide Y Impairs Retrieval of Extinguished Fear and Modulates Excitability of Neurons in the Infralimbic Prefrontal Cortex.

Neuropeptide Y (NPY), a 36 aa peptide, regulates stress and emotional behaviors. Preclinical and clinical studies support an association of NPY with trauma-evoked syndromes such as posttraumatic stress disorder (PTSD), although the exact contribution of NPY is not clear. In the current study, we examined functional attributes of NPY in the infralimbic (IL) cortex, an area that regulates fear memories and is reported to be hypoactive in PTSD. Carriers of NPY gene polymorphism rs16147 have been reported to have elevated prefrontal NPY expression. Infusion of NPY into the IL cortex in rats significantly impaired fear extinction memory without affecting conditioned fear expression or acquisition of extinction. Neuroendocrine stress response, depression-like behavior, and working memory performance were not affected by NPY infusion into the IL. The NPY Y1 receptor antagonist BIBO3304 completely abolished NPY effects on fear extinction retrieval. Y1 receptor expression was localized on CaMKII-positive pyramidal projection neurons and GAD67-positive interneurons in the IL. Patch-clamp recordings revealed increased inhibitory synaptic transmission onto IL projection neurons in the presence of NPY. Thus, NPY dampens excitability of IL projection neurons and impairs retrieval of extinction memory by inhibiting consolidation of extinction. Of relevance to PTSD, elevation of prefrontal NPY attributable to the genetic polymorphism rs16147 may contribute to IL hypoactivity, resulting in impaired extinction memory and susceptibility to the disorder. SIGNIFICANCE STATEMENT: Neuropeptide Y (NPY), a stress modulatory transmitter, is associated with posttraumatic stress disorder (PTSD). Contribution of NPY to PTSD symptomology is unclear. PTSD patients have reduced activity in the infralimbic (IL) subdivision of the medial prefrontal cortex (mPFC), associated with compromised extinction memory. No information exists on fear modulation by NPY in the IL cortex, although NPY and NPY receptors are abundant in these areas. This study shows that IL NPY inhibits consolidation of extinction, resulting in impaired retrieval of extinction memory and modulates excitability of IL projection neurons. In addition to providing a novel perspective on extinction memory modulation by NPY, our findings suggest that elevated mPFC NPY in gene polymorphism rs16147 carriers or after chronic stress could increase susceptibility to PTSD.

A potential role for the acid-sensing T cell death associated gene-8 (TDAG8) receptor in depression-like behavior.

Inflammation has been suggested to contribute to the pathophysiology of depression. The T cell death associated gene-8 (TDAG8) receptor is a proton-sensing G-protein-coupled receptor (GPCR) expressed on immune cells in both the CNS and periphery. Previous work has shown modulation of inflammation by the TDAG8 receptor, with pro-inflammatory responses reported in the central nervous system (CNS). Given the link between depression and inflammation, the aim of the present study was to investigate the role of TDAG8 in depression relevant behaviors. Mice deficient in TDAG8 (TDAG8(-/-)) were tested in the forced swim test (FST) and sucrose preference paradigm. TDAG8 deficiency resulted in significant attenuation of immobility in the FST as compared to wild type TDAG8 (TDAG8(+/+)) mice. These differences were not due to alterations in motor activity evoked by TDAG8 deficiency as TDAG8(+/+) and TDAG8(-/-) mice displayed similar activity in the home cage or in a novel context. TDAG8(-/-) mice showed significantly higher consumption of sucrose compared to wild type mice although sucrose preference was not significantly different between genotypes. Collectively, our results support the involvement of the TDAG8 receptor in behavioral response relevant to depression. Further investigation is required to validate TDAG8 as a novel target linking inflammation and depression.

History of chronic stress modifies acute stress-evoked fear memory and acoustic startle in male rats.

Chronicity of trauma exposure plays an important role in the pathophysiology of posttraumatic stress disorder (PTSD). Thus, exposure to multiple traumas on a chronic scale leads to worse outcomes than acute events. The rationale for the current study was to investigate the effects of a single adverse event versus the same event on a background of chronic stress. We hypothesized that a history of chronic stress would lead to worse behavioral outcomes than a single event alone. Male rats (n = 14/group) were exposed to either a single traumatic event in the form of electric foot shocks (acute shock, AS), or to footshocks on a background of chronic stress (chronic variable stress-shock, CVS-S). PTSD-relevant behaviors (fear memory and acoustic startle responses) were measured following 7 d recovery. In line with our hypothesis, CVS-S elicited significant increases in fear acquisition and conditioning versus the AS group. Unexpectedly, CVS-S elicited reduced startle reactivity to an acoustic stimulus in comparison with the AS group. Significant increase in FosB/ΔFosB-like immunostaining was observed in the dentate gyrus, basolateral amygdala and medial prefrontal cortex of CVS-S rats. Assessments of neuropeptide Y (NPY), a stress-regulatory transmitter associated with chronic PTSD, revealed selective reduction in the hippocampus of CVS-S rats. Collectively, our data show that cumulative stress potentiates delayed fear memory and impacts defensive responding. Altered neuronal activation in forebrain limbic regions and reduced NPY may contribute to these phenomena. Our preclinical studies support clinical findings reporting worse PTSD outcomes stemming from cumulative traumatization in contrast to acute trauma.

Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy.

The dentate gyrus is hypothesized to function as a "gate," limiting the flow of excitation through the hippocampus. During epileptogenesis, adult-generated granule cells (DGCs) form aberrant neuronal connections with neighboring DGCs, disrupting the dentate gate. Hyperactivation of the mTOR signaling pathway is implicated in driving this aberrant circuit formation. While the presence of abnormal DGCs in epilepsy has been known for decades, direct evidence linking abnormal DGCs to seizures has been lacking. Here, we isolate the effects of abnormal DGCs using a transgenic mouse model to selectively delete PTEN from postnatally generated DGCs. PTEN deletion led to hyperactivation of the mTOR pathway, producing abnormal DGCs morphologically similar to those in epilepsy. Strikingly, animals in which PTEN was deleted from ≥ 9% of the DGC population developed spontaneous seizures in about 4 weeks, confirming that abnormal DGCs, which are present in both animals and humans with epilepsy, are capable of causing the disease.