The bed nucleus of the stria terminalis (BNST) is a forebrain region highly responsive to stress that expresses corticotropin-releasing hormone (CRH) and is implicated in mood disorders, such as anxiety. However, the exact mechanism by which chronic stress induces CRH-mediated dysfunction in BNST and maladaptive behaviors remains unclear. Here, we first confirmed that selective acute optogenetic activation of the oval nucleus BNST (ovBNST) increases maladaptive avoidance behaviors in male mice. Next, we found that a 6 week chronic variable mild stress (CVMS) paradigm resulted in maladaptive behaviors and increased cellular excitability of ovBNST CRH neurons by potentiating mEPSC amplitude, altering the resting membrane potential, and diminishing M-currents (a voltage-gated K ϩ current that stabilizes membrane potential) in ex vivo slices. CVMS also increased c-fos ϩ cells in ovBNST following handling. We next investigated potential molecular mechanism underlying the electrophysiological effects and observed that CVMS increased CRH ϩ and pituitary adenylate cyclase-activating polypeptide ϩ (PACAP; a CRH upstream regulator) cells but decreased striatal-enriched protein tyrosine phosphatase ϩ (a STEP CRH inhibitor) cells in ovBNST. Interestingly, the electrophysiological effects of CVMS were reversed by CRHR1-selective antagonist R121919 application. CVMS also activated protein kinase A (PKA) in BNST, and chronic infusion of the PKA-selective antagonist H89 into ovBNST reversed the effects of CVMS. Coadministration of the PKA agonist forskolin prevented the beneficial effects of R121919. Finally, CVMS induced an increase in surface expression of phosphorylated GluR1 (S845) in BNST. Collectively, these findings highlight a novel and indispensable stress-induced role for PKA-dependent CRHR1 signaling in activating BNST CRH neurons and mediating maladaptive behaviors.

This evidence suggests that bilharzial patients with or without bladder tumours and pellagrins infested with S. haematobium suffer from pyridoxine deficiency. Therefore, it is concluded that bilharziasis is not the only causal factor in the associated abnormality of tryptophan metabolism.A main pathway in the degradation of tryptophan is that leading to nicotinic acid formation. This formylkynurenine pathway requires the participation of four vitamins: thiamine, riboflavin, pyridoxine and niacin (Brock, 1961). The known carcinogenic tryptophan metabolites, viz., 3-hydroxykynurenine, xanthurenic acid, 8-methyl ether of xanthurenic acid, 8-hydroxyquinaldic acid, 3-hydroxyanthranilic acid and 2-amino-3-hydroxyacetophenone (Boyland and Watson, 1956;Allen et al., 1957;Bryan et al., 1964), are formed through this pathway. The urinary excretion of these metabolites by patients with bladder neoplasms and other diseases has been investigated (Brown et al., 1955;Boyland and Williams, 1956; Price, 1958;Brown et al., 1960;Price and Brown, 1962; and Wallace and White, 1963).In our laboratories, attention is directed towards pellagra and bil harziasis as possible zetiological factors of bladder carcinoma in the UAR. In the present paper we report the results of further studies on tryptophan metabolites in the urine of bilharzial bladder cancer patients as compared with those suffering from simple vesical bilharziasis and with pellagrins infested with the same parasite. MATERIAL AND METHODSTwenty-four-hour urines from the following groups were investigated : ( a ) Eight normal human subjects comprising laboratory personnel ranging in age from 20 to 40 years.

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