Murat S. Durakoglugil, Catherine R. Wasser, Connie H. Wong, Theresa Pohlkamp, Xunde Xian, et al. (see pages [7340–7349][1]) Long-term depression (LTD) of synaptic strength is an important component of synaptic plasticity and is required for certain types of learning and behavioral flexibility.

Post-tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knock-in mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1SA mice), and we studied mice of either sex. The expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3-to-CA1 synapse and the granule cell parallel fiber (PF)-to-Purkinje cell (PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic the activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1SA mice. I...

Neuron migration is a hallmark of nervous system development that allows gathering of neurons from different origins for assembling of functional neuronal circuits. Cortical inhibitory interneurons arise in the ventral telencephalon and migrate tangentially forming three transient migratory streams in the cortex before reaching the final laminar destination. Although migration defects lead to the disruption of inhibitory circuits and are linked to aspects of psychiatric disorders such as autism and schizophrenia, the molecular mechanisms controlling cortical interneuron development and final layer positioning are incompletely understood. Here, we show that mouse embryos with a double deletion of FLRT2 and FLRT3 genes encoding cell adhesion molecules exhibit an abnormal distribution of interneurons within the streams during development, which in turn, affect the layering of somatostatin+ interneurons postnatally. Mechanistically, FLRT2 and FLRT3 proteins act in a noncell-autonomous manner, possibly through ...

Neurons in the PFC are typically activated by different cognitive tasks, and also by different stimuli and abstract variables within these tasks. A single neuron's selectivity for a given stimulus dimension often changes depending on its context, a phenomenon known as nonlinear mixed selectivity (NMS). It has previously been hypothesized that NMS emerges as a result of training to perform tasks in different contexts. We tested this hypothesis directly by examining the neuronal responses of different PFC areas before and after male monkeys were trained to perform different working memory tasks involving visual stimulus locations and/or shapes. We found that training induces a modest increase in the proportion of PFC neurons with NMS exclusively for spatial working memory, but not for shape working memory tasks, with area 9/46 undergoing the most significant increase in NMS cell proportion. We also found that increased working memory task complexity, in the form of simultaneously storing location and shape c...

Both nucleus reuniens and the anterior thalamic nuclei are densely interconnected with medial cortical and hippocampal areas, connections that reflect their respective contributions to learning and memory. To better appreciate their comparative roles, pairs of different retrograde tracers were placed in these two thalamic sites in adult rats. Both thalamic sites receive modest cortical inputs from layer V that contrasted with much denser projections from layer VI. Despite frequent overlap in layer VI, ventral prefrontal and anterior cingulate inputs to nucleus reuniens were concentrated in the deepest sublayer (VIb). Meanwhile, inputs to the anterior thalamic nuclei originated more evenly from both sublayers VIa and VIb, with the result that they were often located more superficially than the projections to nucleus reuniens. Again, while the many hippocampal (subiculum) neurons projecting to nucleus reuniens and the anterior thalamic nuclei were partially intermingled within the deep cellular parts of the ...

The ability to measure changes in neuronal activity in a quantifiable and precise manner is of fundamental importance to understand neuron development and function. Repeated monitoring of neuronal activity of the same population of neurons over several days is challenging and, typically, low-throughput. Here, we describe a new biochemical reporter assay that allows for repeated measurements of neuronal activity in a cell type-specific manner. We coupled activity-dependent elements from the Arc/Arg3.1 gene with a secreted reporter, Gaussia luciferase (Gluc), to quantify neuronal activity without sacrificing the neurons. The reporter predominantly senses calcium and NMDA receptor (NMDAR)-dependent activity. By repeatedly measuring the accumulation of the reporter in cell media, we can profile the developmental dynamics of neuronal activity in cultured neurons from male and female mice. The assay also allows for longitudinal analysis of pharmacological treatments, thus distinguishing acute from delayed respon...

The hedgehog signaling pathway is best known for its role in developmental patterning of the neural tube and limb bud. More recently, hedgehog signaling has been recognized for its roles in growth of adult tissues and maintenance of progenitor cell niches. However, the role of hedgehog signaling in fully differentiated cells like neurons in the adult brain is less clear. In mammals, coordination of hedgehog pathway activity relies on primary cilia and patients with ciliopathies such as Bardet–Biedl and Alström syndrome exhibit clinical features clearly attributable to errant hedgehog such as polydactyly. However, these ciliopathies also present with features not clearly associated with hedgehog signaling such as hyperphagia-associated obesity. How hedgehog signaling may contribute to feeding behavior is complex and unclear, but cilia are critical for proper energy homeostasis. Here, we provide a detailed analysis of the expression of core components of the hedgehog signaling pathway in the adult mouse hypo...

Most human movements require coordinated activation of multiple muscles. Although many studies reported associations between arm, leg, and trunk muscles during functional tasks, their neural interaction mechanisms still remain unclear. Therefore, the aim of our study was to investigate arm-trunk or arm-leg neural interactions in the corticospinal tract during different arm muscle contractions. Specifically, we examined corticospinal excitability of the erector spinae (ES; trunk extensor), rectus abdominis (RA; trunk flexor), and tibialis anterior (TA; leg) muscles while participants exerted: (1) wrist flexion and (2) wrist extension isometric contraction at various contraction intensity levels ranging from rest to 50% of maximal voluntary contraction (MVC) effort. Corticospinal excitability was assessed using motor evoked potentials (MEPs) elicited through motor cortex transcranial magnetic stimulation (TMS). Results showed that ES MEPs were facilitated even at low contractions (>5% MVC) during wrist flexi...

Neuroendocrine control of reproduction is disrupted in many individuals with polycystic ovary syndrome (PCOS), who present with increased luteinizing hormone (LH), and presumably gonadotropin-releasing hormone (GnRH), release frequency, and high androgen levels. Prenatal androgenization (PNA) recapitulates these phenotypes in primates and rodents. Female offspring of mice injected with dihydrotestosterone (DHT) on gestational days 16–18 exhibit disrupted estrous cyclicity, increased LH and testosterone, and increased GnRH neuron firing rate as adults. PNA also alters the developmental trajectory of GnRH neuron firing rates, markedly blunting the prepubertal peak in firing that occurs in three-week (3wk)-old controls. GnRH neurons do not express detectable androgen receptors and are thus probably not the direct target of DHT. Rather, PNA likely alters GnRH neuronal activity by modulating upstream neurons, such as hypothalamic arcuate neurons co-expressing kisspeptin, neurokinin B (gene Tac2), and dynorphin,...

Social connections in gregarious species are vital for safety and survival. For these reasons, many bird species form large flocks outside the breeding season. It has been proposed that such large social groups may be maintained via reward induced by positive interactions with conspecifics and via the reduction of a negative affective state caused by social separation. Moreover, within a flock optimal social spacing between conspecifics is important, indicating that individuals may optimize spacing to be close but not too close to conspecifics. The μ-opioid receptors (MORs) in the nucleus accumbens (NAc) are well known for their role in both reward and the reduction of negative affective states, suggesting that MOR stimulation in NAc may play a critical role in flock cohesion. To begin to test this hypothesis, social and nonsocial behaviors were examined in male and female European starlings ( Sturnus vulgaris ) in nonbreeding flocks after intra-NAc infusion of saline and three doses of the selective MOR a...