Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation

Impact of prostate cancer treatment on pelvic nerve injury and erectile function

Following prostate cancer treatment, many men will experience urogenital side effects including erectile dysfunction (ED), a condition significantly affecting survivor quality of life. The cause of ED after treatment is frequently unknown, but injury to the inferior hypogastric plexus, a collection of nerves adjacent to the prostate that control significant urogenital function such as erection, is often implicated. In this work, we examined the effect of three different prostate cancer treatments: external beam radiation therapy (RT) alone, and androgen deprivation therapy (ADT) and radical prostatectomy (RP) both alone and in combination, on erectile function, penile physiology and neuronal health in male rats. These studies examined neurons from the major pelvic ganglia (MPG) in rodents, the correlate of the human inferior hypogastric plexus. Adult male Sprague-Dawley rats underwent prostate-confined, conformal, single fraction 22 Gy RT or sham treatment. Erectile function was assessed by cavernous nerve stimulated intracavernosal to mean arterial pressure (ICP/MAP) measurement and penile smooth muscle function was assessed at 2 or 10 weeks post-RT. MPGs were dissociated and neurons grown in culture to examine axon length and branching, and neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH) and TUNEL assay expression. MPG gene expression for neuron type, and markers of nerve injury and repair were measured. Although rats did not demonstrate ED post-RT, they did have impaired penile contraction. Pelvic neurons demonstrated chronic decreases in neuron length, branching and TH positive cells, as well as progressive neuronal apoptosis and loss of nNOS positive neurons. Markers of synaptic remodeling were increased at 10 weeks while genes related to nerve repair and regeneration were decreased. This is the first study to characterize the health and regeneration potential of dissociated MPG neurons following RT. Neuronal injury was apparent early post-RT and persisted or increased over time. The nerves are very susceptible to apoptosis and damage from prostatic RT, but even with significant injury, this model did not cause ED. In our second study, adult Sprague-Dawley rats were castrated (CAST) and experienced 4 weeks of androgen deprivation before undergoing bilateral cavernous nerve injury (BCNI). This paradigm mimics human patients undergoing ADT before RP and we would expect the combination to increase the severity of ED. At the time of BCNI, some rats received 2 weeks of supplemental testosterone to rescue erectile function and repair nerves. Rats undergoing CAST and BCNI demonstrated significantly decreased ICP/MAP that was further exacerbated in the both castrated and nerve injured (C+B) group. Penile contraction was markedly increased with CAST and C+B to endothelin-1, phenylephrine and electrical field stimulation (EFS). Additionally, relaxation was impaired to nitric oxide donors and non-adrenergic non-cholinergic EFS. Exogenous androgens restored normal erectile function in CAST, BCNI and C+B groups. Similarly, testosterone supplementation returned penile smooth muscle vasoreactivity to control levels. In cultured MPG neurons, C+B induced the greatest amount of apoptosis and had the fewest nNOS positive cells. Testosterone administration prevented the increase in apoptotic cells and restored nNOS positive neuron populations. Furthermore, testosterone increased both TH positive cells and neurite length, but had no effect on neurite branching. These data demonstrate increased MPG neuron injury during ADT that could be ameliorated with testosterone supplementation. Overall, this work demonstrates that prostate cancer treatments are causing significant damage to the surrounding pelvic neuronal structures and leading to penile smooth muscle dysfunction and ED. Furthermore, therapeutic strategies are required to preserve both the functional and structural integrity of the cavernous nerve and MPG to prevent and/or rescue ED in men with prostate cancer

Impact of prostate cancer treatment on pelvic nerve injury and erectile function

Following prostate cancer treatment , many men will experience urogenital side effects including erectile dysfunction (ED) , a condition significantly affecting survivor quality of life. The cause of ED after treatment is frequently unknown , but injury to the inferior hypogastric plexus , a collection of nerves adjacent to the prostate that control significant urogenital function such as erection , is often implicated. In this work , we examined the effect of three different prostate cancer treatments: external beam radiation therapy (RT) alone , and androgen deprivation therapy (ADT) and radical prostatectomy (RP) both alone and in combination , on erectile function , penile physiology and neuronal health in male rats. These studies examined neurons from the major pelvic ganglia (MPG) in rodents , the correlate of the human inferior hypogastric plexus. Adult male Sprague-Dawley rats underwent prostate-confined , conformal , single fraction 22 Gy RT or sham treatment. Erectile function was assessed by cavernous nerve stimulated intracavernosal to mean arterial pressure (ICP/MAP) measurement and penile smooth muscle function was assessed at 2 or 10 weeks post-RT. MPGs were dissociated and neurons grown in culture to examine axon length and branching , and neuronal nitric oxide synthase (nNOS) , tyrosine hydroxylase (TH) and TUNEL assay expression. MPG gene expression for neuron type , and markers of nerve injury and repair were measured. Although rats did not demonstrate ED post-RT , they did have impaired penile contraction. Pelvic neurons demonstrated chronic decreases in neuron length , branching and TH positive cells , as well as progressive neuronal apoptosis and loss of nNOS positive neurons. Markers of synaptic remodeling were increased at 10 weeks while genes related to nerve repair and regeneration were decreased. This is the first study to characterize the health and regeneration potential of dissociated MPG neurons following RT. Neuronal injury was apparent early post-RT and persisted or increased over time. The nerves are very susceptible to apoptosis and damage from prostatic RT , but even with significant injury , this model did not cause ED. In our second study , adult Sprague-Dawley rats were castrated (CAST) and experienced 4 weeks of androgen deprivation before undergoing bilateral cavernous nerve injury (BCNI). This paradigm mimics human patients undergoing ADT before RP and we would expect the combination to increase the severity of ED. At the time of BCNI , some rats received 2 weeks of supplemental testosterone to rescue erectile function and repair nerves. Rats undergoing CAST and BCNI demonstrated significantly decreased ICP/MAP that was further exacerbated in the both castrated and nerve injured (C+B) group. Penile contraction was markedly increased with CAST and C+B to endothelin-1 , phenylephrine and electrical field stimulation (EFS). Additionally , relaxation was impaired to nitric oxide donors and non-adrenergic non-cholinergic EFS. Exogenous androgens restored normal erectile function in CAST , BCNI and C+B groups. Similarly , testosterone supplementation returned penile smooth muscle vasoreactivity to control levels. In cultured MPG neurons , C+B induced the greatest amount of apoptosis and had the fewest nNOS positive cells. Testosterone administration prevented the increase in apoptotic cells and restored nNOS positive neuron populations. Furthermore , testosterone increased both TH positive cells and neurite length , but had no effect on neurite branching. These data demonstrate increased MPG neuron injury during ADT that could be ameliorated with testosterone supplementation. Overall , this work demonstrates that prostate cancer treatments are causing significant damage to the surrounding pelvic neuronal structures and leading to penile smooth muscle dysfunction and ED. Furthermore , therapeutic strategies are required to preserve both the functional and structural integrity of the cavernous nerve and MPG to prevent and/or rescue ED in men with prostate cancer

Impaired contraction and decreased detrusor innervation in a female rat model of pelvic neuropraxia

Introduction and hypothesis: Bilateral pelvic nerve injury (BPNI) is a model of post-radical hysterectomy neuropraxia, a common sequela. This study assessed the time course of changes to detrusor autonomic innervation, smooth muscle (SM) content and cholinergic-mediated contraction post-BPNI. Methods: Female Sprague–Dawley rats underwent BPNI or sham surgery and were evaluated 3, 7, 14, and 30 days post-BPNI (n = 8/group). Electrical field-stimulated (EFS) and carbachol-induced contractions were measured. Gene expression was assessed by qPCR for muscarinic receptor types 2 (M2) and 3 (M3), collagen type 1α1 and 3α1, and SM actin. Western blots measured M2 and M3 protein expression. Bladder sections were stained with Masson’s trichrome for SM content and immunofluorescence staining for nerve terminals expressing vesicular acetylcholine transporter (VAChT), tyrosine hydroxylase (TH), and neuronal nitric oxide synthase (nNOS). Results: Bilateral pelvic nerve injury caused larger bladders with less SM content and increased collagen type 1α1 and 3α1 gene expression. At early time points, cholinergic-mediated contraction increased, whereas EFS-mediated contraction decreased and returned to baseline by 30 days. Protein and gene expression of M3 was decreased 3 and 7 days post-BPNI, whereas M2 was unchanged. TH nerve terminals surrounding the detrusor decreased in all BPNI groups, whereas VAChT and nNOS terminals decreased 14 and 30 days post-BPNI. Conclusions: Bilateral pelvic nerve injury increased bladder size, impaired contractility, and decreased SM and autonomic innervation. Therapeutic strategies preventing nerve injury-mediated decline in neuronal input and SM content may prevent the development of a neurogenic bladder and improve quality of life after invasive pelvic surgery