The peak procedure was used to characterize response timing during acquisition and maintenance of conditioned responding in goldfish. Subjects received light-shock pairings with a 5- or 15-s interstimulus interval. On interspersed peak trials, the conditioned stimulus light was presented for 45 s and no shock was delivered. Peaks in the conditioned response, general activity, occurred at about the time of the expected unconditioned stimulus, and variability in the activity distribution was scalar. Modeling of the changes in the activity distributions over sessions revealed that the temporal features of the conditioned response changed very little during acquisition. The data suggest that times are learned early in training, and, contrary to I. P. Pavlov's (1927/1960) concept of "inhibition of delay," that timing is learning when to respond rather than learning when not to respond.

Thousands of children receive methylphenidate (MPH; Ritalin) for attention deficit/hyperactivity disorder (ADHD), yet the long-term neurochemical consequences of MPH treatment are unknown. To mimic clinical Ritalin treatment in children, male rats were injected with MPH (5 mg/kg) or vehicle twice daily from postnatal day 7 (PND7)-PND35. At the end of administration (PND35) or in adulthood (PND135), brain sections from littermate pairs were immunocytochemically labeled for neurotransmitters and cytological markers in 16 regions implicated in MPH effects and/or ADHD etiology. At PND35, the medial prefrontal cortex (mPFC) of rats given MPH showed 55% greater immunoreactivity (-ir) for the catecholamine marker tyrosine hydroxylase (TH), 60% more Nissl-stained cells, and 40% less norepinephrine transporter (NET)-ir density. In hippocampal dentate gyrus, MPH-receiving rats showed a 51% decrease in NET-ir density and a 61% expanded distribution of the new-cell marker PSA-NCAM (polysialylated form of neural cell adhesion molecule). In medial striatum, TH-ir decreased by 21%, and in hypothalamus neuropeptide Y-ir increased by 10% in MPH-exposed rats. At PND135, MPH-exposed rats exhibited decreased anxiety in the elevated plus-maze and a trend for decreased TH-ir in the mPFC. Neither PND35 nor PND135 rats showed major structural differences with MPH exposure. These findings suggest that developmental exposure to high therapeutic doses of MPH has short-term effects on select neurotransmitters in brain regions involved in motivated behaviors, cognition, appetite, and stress. Although the observed neuroanatomical changes largely resolve with time, chronic modulation of young brains with MPH may exert effects on brain neurochemistry that modify some behaviors even in adulthood.

Depression, anxiety and conduct disorders are common in children and adolescents and selective serotonin reuptake inhibitors (SSRIs) are often used to treat these conditions. Fluoxetine (Prozac) is the first approved SSRI for the treatment of depression in this population. Although it is believed that overall, fluoxetine is effective in child and adolescent psychiatry, there have been reports of specific adverse drug effects; most prominently suicidality and psychiatric symptoms such as agitation, worsening of depression and anxiety. Chronic fluoxetine substantially increases brain extracellular 5-HT concentrations and the juvenile developing brain may respond to supraphysiological 5-HT levels with specific adverse effects not seen or less prominent in adult brain. Using novelty induced hypophagia (NIH), as well as open field (OF) and elevated plus maze (EPM) tests, we show that both Swiss Webster (SW) and C57Bl/6 (B6) mice, receiving fluoxetine in a clinically relevant dose and during their juvenile age corresponding to child-adolescent period in human, exhibit a paradoxical anxiogenic response. The adverse effects of juvenile fluoxetine disappeared upon drug discontinuation and no long term behavioral consequences were apparent. No adverse effect to chronic fluoxetine was seen in adult mice and a dose dependent anxiolytic effect developed. These data show that the age of the mice, independently of the strains and tests used in this study, is the determining factor of whether the response to chronic fluoxetine is anxiolytic or anxiogenic. Taken together, the response of the juvenile and adult brain to fluoxetine could be fundamentally different and the juvenile fluoxetine administration mouse model described here may help to identify the mechanism underlying this difference.

Na+-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. Here, we found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K+ channel β subunit, showed a reduction in the myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum. Increased behavorial responsiveness to stress and seizure susceptibility in Kcne2−/− mice were alleviated by injections of myo-inositol. Suspecting a defect in myo-inositol transport, we found that KCNE2 and KCNQ1, a voltage-gated potassium channel α subunit, colocalized and coimmunoprecipitated with SMIT1, a Na+-coupled myo-inositol transporter, in the choroid plexus epithelium. Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 but inhibited by coexpression of both KCNQ1 and KCNE2, which form a constitutively active, heteromeric K+ channel. SMIT1 and the related transporter SMIT2 were also inhibited by a constitutively active mutant form of KCNQ1. The activity of KCNQ1 and KCNQ1-KCNE2 were augmented by SMIT1 and the glucose transporter SGLT1, but suppressed by SMIT2. Channel-transporter signaling complexes may be a widespread mechanism to facilitate solute transport and electrochemical crosstalk.

Low serotonin 1A receptor (5-HT 1A R) binding is a risk factor for anxiety and depression, and deletion of the 5-HT 1A R results in anxiety-like behavior in mice. Here we show that anxiety-like behavior in mice also can be caused, independently of the offspring's own 5-HT 1A R genotype, by a receptor deficit in the mother: a nongenetic transmission of a genetic defect. Some of the nongenetically transmitted anxiety manifestations were acquired prenatally and linked to a delay in dentate gyrus maturation in the ventral hippocampus of the offspring. Both the developmental delay and the anxiety-like phenotype were phenocopied by the genetic inactivation of p16 ink4a encoding a cyclin-dependent kinase inhibitor implicated in neuronal precursor differentiation. No maternal 5-HT 1A R genotype-dependent anxiety developed when the strain background was switched from Swiss Webster to C57BL/6, consistent with the increased resilience of this strain to early adverse environment. Instead, all anxiety manifestations were caused by the offspring's own receptor deficiency, indicating that the genetic and nongenetic effects converge to common anxiety manifestations. We propose that 5-HT 1A R deficit represents a dual risk for anxiety and that vulnerability to anxiety associated with genetic 5-HT 1A R deficiency can be transmitted by both genetic and nongenetic mechanisms in a population. Thus, the overall effect of risk alleles can be higher than estimated by traditional genetic assays and may contribute to the relatively high heritability of anxiety and psychiatric disorders in general.genetic risk | heritability | cross-fostering S tudies have identified mutant/polymorphic variants of genes, each with a relatively small contribution to the risk of depression, anxiety, schizophrenia, and other psychiatric diseases. However, demonstrable genetic influences explain only a small fraction of estimated heritability in psychiatric conditions. This "missing heritability" could be caused by a large number of undiscovered alleles or by mechanisms that amplify the effect of risk alleles but are not genetic in nature. We tested the hypothesis that mutant/polymorphic variants can have a larger effect if, besides their purely genetic effect, they have an additional "environmental" effect. For example, gene variants could influence maternal physiology, affecting the developmental program of the offspring, and consequently also increasing the risk for psychopathology. Indeed, adverse prenatal maternal and/or postnatal environment increases vulnerability to various diseases, including psychiatric disorders, in adulthood (1, 2), and one may extrapolate these findings to an abnormal maternal/parental environment related to disease-associated genes/gene variants.One of the few candidate genes whose function has been associated with anxiety and depression encodes the serotonin 1A receptor (5-HT 1A R) (3). Reduced binding or binding potential in the 5-HT 1A R has been linked to posttraumatic stress and panic disorders (3) and depression (4), and a...