SUMMARY Non cell-autonomous processes are thought to play critical roles in the cellular maintenance of the healthy and diseased brain but mechanistic details remain unclear. We report that the interruption of a non-cell autonomous mode of sonic hedgehog (Shh) signaling originating from dopaminergic neurons causes progressive, adult-onset degeneration of dopaminergic, cholinergic, and fast spiking GABAergic neurons of the mesostriatal circuit, imbalance of cholinergic and dopaminergic neurotransmission, and motor deficits reminiscent of Parkinson’s disease. Variable Shh signaling results in graded inhibition of muscarinic auto-receptor- and GDNF- expression in the striatum. Reciprocally, graded signals that emanate from striatal cholinergic neurons and engage the canonical GDNF receptor Ret inhibit Shh expression in dopaminergic neurons. Thus, we discovered a novel mechanism for neuronal subtype specific and reciprocal communication that is essential for neurochemical and structural homeostasis in the nigrostriatal circuit. These results provide integrative insights into non cell-autonomous processes likely at play in neurodegenerative conditions such as Parkinson’s disease.

Neuregulin-1 (NRG-1) is genetically linked with schizophrenia, a neurodevelopmental cognitive disorder characterized by imbalances in glutamatergic and dopaminergic function. NRG-1 regulates numerous neurodevelopmental processes and, in the adult, suppresses or reverses long-term potentiation (LTP) at hippocampal glutamatergic synapses. Here we show that NRG-1 stimulates dopamine release in the hippocampus and reverses early-phase LTP via activation of D4 dopamine receptors (D4R). NRG-1 fails to depotentiate LTP in hippocampal slices treated with the antipsychotic clozapine and other more selective D4R antagonists. Moreover, LTP is not depotentiated in D4R null mice by either NRG-1 or theta-pulse stimuli. Conversely, direct D4R activation mimics NRG-1 and reduces AMPA receptor currents and surface expression. These findings demonstrate that NRG-1 mediates its unique role in counteracting LTP via dopamine signaling and opens future directions to study new aspects of NRG function. The novel functional link between NRG-1, dopamine, and glutamate has important implications for understanding how imbalances in Neuregulin-ErbB signaling can impinge on dopaminergic and glutamatergic function, neurotransmitter pathways associated with schizophrenia.depotentiation ͉ ErbB receptor ͉ plasticity ͉ schizophrenia ͉ clozapine T he trophic and differentiation factor NRG-1 and its receptors (ErbB2-4) are expressed in the developing nervous system and adult brain, including the hippocampus. NRG-1 is translated as a transmembrane protein and released in an activity-dependent manner (1). Initially, long-term NRG-1 signaling was shown to regulate neuronal expression of neurotransmitter receptor genes for glutamate, acetylcholine, and GABA (2-5). More recently, the tight association of the NRG-1 receptor ErbB4 with glutamate receptors at postsynaptic densities suggested that NRG-1 signaling could regulate synaptic function in a more acute fashion (6, 7). Consistent with this idea, we and others have shown that NRG-1␤ rapidly regulates glutamatergic (7-11) and cholinergic (12) synaptic function in the hippocampus and prefrontal cortex (PFC).Long term potentiation (LTP) and long term depression (LTD) at Schaeffer collateral-to-CA1 hippocampal synapses (SC-CA1) are believed to underlie complex cognitive processes such as learning and memory. At this synapse, postsynaptic NMDAR activation and increases in AMPAR excitatory postsynaptic currents (EPSCs) are necessary for LTP induction and expression, respectively. An additional mechanism that contributes to synaptic homeostasis at adult glutamatergic synapses is depotentiation (13,14). In acute hippocampal slices and in freely moving animals, LTP is reversed (depotentiated) by brief, subthreshold theta pulse stimulation (TPS) if delivered during a labile period shortly after LTP induction (14). In the amygdala, depotentiation correlates with fear extinction and requires AMPAR internalization (15). We recently reported that NRG-1␤ depotentiates early-phase LTP at hippocampal SC-CA1 synapses,...

Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

Brain-derived neurotrophic factor (BDNF) regulates diverse biological functions ranging from neuronal survival and differentiation during development to synaptic plasticity and cognitive behavior in the adult. BDNF disruption in both rodents and humans is associated with neurobehavioral alterations and psychiatric disorders. A unique feature of Bdnf transcription is regulation by nine individual promoters, which drive expression of variants that encode an identical protein. It is hypothesized that this unique genomic structure may provide flexibility that allows different factors to regulate BDNF signaling in distinct cell types and circuits. This has led to the suggestion that isoforms may regulate specific BDNF-dependent functions; however, little scientific support for this idea exists. We generated four novel mutant mouse lines in which BDNF production from one of the four major promoters (I, II, IV, or VI) is selectively disrupted (Bdnf-e1, -e2, -e4, and -e6 mice) and used a comprehensive comparator approach to determine whether different Bdnf transcripts are associated with specific BDNF-dependent molecular, cellular, and behavioral phenotypes. Bdnf-e1 and -e2 mutant males displayed heightened aggression accompanied by convergent expression changes in specific genes associated with serotonin signaling. In contrast, BDNF-e4 and -e6 mutants were not aggressive but displayed impairments associated with GABAergic gene expression. Moreover, quantifications of BDNF protein in the hypothalamus, prefrontal cortex, and hippocampus revealed that individual Bdnf transcripts make differential, regionspecific contributions to total BDNF levels. The results highlight the biological significance of alternative Bdnf transcripts and provide evidence that individual isoforms serve distinct molecular and behavioral functions.

Background-Abnormal hedonic behavior is a key feature of many psychiatric disorders. Several paradigms measure reward-seeking behavior in rodents, but each has limitations. We describe a novel approach for monitoring reward-seeking behavior in rodents: sniffing of estrus female urine by male mice, along with number of ultrasonic vocalizations (USVs) emitted during the test.

Rationale Myogenic tone, an important regulator of vascular resistance, is dependent on vascular smooth muscle (VSM) depolarization, can be modulated by endothelial factors, and is increased in several models of hypertension. Intermittent hypoxia (IH) elevates blood pressure and causes endothelial dysfunction. Hydrogen sulfide (H2S), a recently described endothelium-derived vasodilator, is produced by the enzyme cystathionine γ-lyase (CSE) and acts by hyperpolarizing VSM. Objective Determine whether IH decreases endothelial H2S production to increase myogenic tone in small mesenteric arteries. Methods and Results Myogenic tone was greater in mesenteric arteries from IH than Shamfrom sham rat arteries, and VSM membrane potential was depolarized in IH in comparison with Shamsham arteries. Endothelium inactivation or scavenging of H2S enhanced myogenic tone in Shamsham arteries to the level of IH. Inhibiting CSE also enhanced myogenic tone and depolarized VSM in Shamsham but not IH arteries. Similar results were seen in cerebral arteries. Exogenous H2S dilated and hyperpolarized Shamsham and IH arteries, and this dilation was blocked by iberiotoxin, paxilline, and KCl preconstriction but not glibenclamide or 3-isobutyl-1-methylxanthine. Iberiotoxin enhanced myogenic tone in both groups but more in Shamsham than IH. CSE immunofluorescence was less in the endothelium of IH than in Shamsham mesenteric arteries. Endogenouse H2S dilation was reduced in IH arteries. Conclusions IH appears to decrease endothelial CSE expression to reduce H2S production, depolarize VSM, and enhance myogenic tone. H2S dilatation and hyperpolarization of VSM in small mesenteric arteries requires BKCa channels.

The effect of roasting of Sacha-inchi (Plukenetia volubilis L.) seeds on the oxidative stability and composition of its oil was investigated. The seeds were subjected to light, medium and high roasting intensities. Oil samples were subjected to high-temperature storage at 60 °C for 30 days and evaluated for oxidation (peroxide value and p-anisidine), antioxidant activity (total phenols and DPPH assay), and composition (tocopherol content and fatty acid profile). Results showed that roasting partially increased oil oxidation and its antioxidant capacity, slightly decreased tocopherol content, and did not affect the fatty acid profile. During storage, oxidation increased for all oil samples, but at a slower rate for oils from roasted seeds, likely due to its higher antioxidant capacity. Also, tocopherol content decreased significantly, and a slight modification of the fatty acid profile suggested that α-linolenic acid oxidized more readily than other fatty acids present.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder for which there is no successful prevention or intervention. The pathological hallmark for PD involves the self-assembly of functional Alpha-Synuclein (αS) into non-functional amyloid structures. One of the potential therapeutic interventions against PD is the effective inhibition of αS aggregation. However, the bottleneck towards achieving this goal is the identification of αS domains/sequences that are essential for aggregation. Using a protein mimetic approach, we have identified αS sequences-based targets that are essential for aggregation and will have significant therapeutic implications. An extensive array of in vitro, ex vivo, and in vivo assays is utilized to validate αS sequences and their structural characteristics that are essential for aggregation and propagation of PD phenotypes. The study aids in developing significant mechanistic and therapeutic insights into various facets of αS aggregation, which will pave the way for effective treatments for PD.