Brain-derived neurotropic factor (BDNF) has been shown to play critical roles in neural development, plasticity, and neurodegenerative diseases. The main function of BDNF in the brain is widely accepted to be synaptic regulation. However, how BDNF modulates synaptic transmission, especially the underlying signaling cascades between presynaptic and postsynaptic neurons, remains controversial. In the present study, we investigated the actions of BDNF at rat calyx-type synapses of either sex by measuring the excitatory postsynaptic current (EPSC) and presynaptic calcium current and capacitance changes. We found that BDNF inhibits the EPSC, presynaptic calcium influx, and exocytosis/endocytosis via activation of the presynaptic cannabinoid Type 1 receptors (CB1Rs). Inhibition of the CB1Rs abolished the BDNF-induced presynaptic inhibition, whereas CB1R agonist mimicked the effect of BDNF. Exploring the underlying signaling cascade, we found that BDNF specifically activates the postsynaptic TrkB receptors, induc...

The amyloid-β (Aβ) peptide, a key pathogenic factor in Alzheimer's disease, attenuates the increase in cerebral blood flow (CBF) evoked by neural activity (functional hyperemia), a vital homeostatic response in which NMDA receptors (NMDARs) play a role through nitric oxide, and the CBF increase produced by endothelial factors. Tissue plasminogen activator (tPA), which is reduced in Alzheimer's disease and in mouse models of Aβ accumulation, is required for the full expression of the NMDAR-dependent component of functional hyperemia. Therefore, we investigated whether tPA is involved in the neurovascular dysfunction of Aβ. tPA activity was reduced, and the tPA inhibitor plasminogen inhibitor-1 (PAI-1) was increased in male mice expressing the Swedish mutation of the amyloid precursor protein (tg2576). Counteracting the tPA reduction with exogenous tPA or with pharmacological inhibition or genetic deletion of PAI-1 completely reversed the attenuation of the CBF increase evoked by whisker stimulation but did ...

Interstitial axon branching is an essential step during the establishment of neuronal connectivity. However, the exact mechanisms on how the number and position of branches are determined are still not fully understood. Here, we investigated the role of Arl8B, an adaptor molecule between lysosomes and kinesins. In chick retinal ganglion cells (RGCs), downregulation of Arl8B reduces axon branch density and shifts their location more proximally, while Arl8B overexpression leads to increased density and more distal positions of branches. These alterations correlate with changes in the location and density of lysosomes and autophagosomes along the axon shaft. Diminishing autophagy directly by knock-down of atg7, a key autophagy gene, reduces branch density, while induction of autophagy by rapamycin increases axon branching, indicating that autophagy plays a prominent role in axon branch formation. In vivo , local inactivation of autophagy in the retina using a mouse conditional knock-out approach disturbs reti...

One of the notable characteristics of the functional localization in the cerebellar cortex is the dual representation of the body (somatotopy) along with its anterior-posterior axis. This somatotopy is conspicuous in the C1/C3 module, which is demarcated as the multiple zebrin-negative and weekly-positive stripes in dual paravermal areas in anterior and posterior lobules within the cerebellar compartments. In this report, we describe the early formation process of the cerebellar compartmentalization, particularly in the C1/C3 module. As developing PCs guide formation of the module-specific proper neuronal circuits in the cerebellum, we hypothesized that the rearrangement of embryonic Purkinje cell (PC) clusters shapes the adult cerebellar compartmentalization. By identifying PC clusters with immunostaining of marker molecules and genetical birthdate-tagging with Neurog2 -CreER (G2A) mice, we clarified the three-dimensional spatial organization of the PC clusters and tracked the lineage relationships among ...

Thomas A. Ravenscroft, Jasper Janssens, Pei-Tseng Lee, Burak Tepe, Paul C. Marcogliese, et al. (see pages [7999–8024][1]) The iconic neuron is multipolar, with several dendrites and a single axon emerging from the cell body. Near the base of the axon, a region called the axon initial segment (

In multipolar vertebrate neurons, action potentials (APs) initiate close to the soma, at the axonal initial segment. Invertebrate neurons are typically unipolar with dendrites integrating directly into the axon. Where APs are initiated in the axons of invertebrate neurons is unclear. Voltage-gated sodium (NaV) channels are a functional hallmark of the axonal initial segment in vertebrates. We used an intronic Minos -Mediated Integration Cassette to determine the endogenous gene expression and subcellular localization of the sole NaV channel in both male and female Drosophila , para . Despite being the only NaV channel in the fly, we show that only 23 ± 1% of neurons in the embryonic and larval CNS express para , while in the adult CNS para is broadly expressed. We generated a single-cell transcriptomic atlas of the whole third instar larval brain to identify para expressing neurons and show that it positively correlates with markers of differentiated, actively firing neurons. Therefore, only 23 ± 1% of lar...

Chronic pain is a complex neurologic condition that involves both sensory and affective components. A crucial integrator of pain-related sensation and affect may be a set of neurons within the parabrachial nucleus. This area receives nociceptive inputs from spinal projection neurons and transmits

In the article “Alzheimer's Disease-Like Pathology Induced by Amyloid-β Oligomers in Nonhuman Primates,” by Leticia Forny-Germano, Natalia M. Lyra e Silva, André F. Batista, Jordano Brito-Moreira, Matthias Gralle, Susan E. Boehnke, Brian C. Coe, Ann Lablans, Suelen A. Marques, Ana Maria B.

When we move the features of our face, or turn our head, we communicate changes in our internal state to the people around us. How this information is encoded and used by an observer's brain is poorly understood. We investigated this issue using a functional MRI adaptation paradigm in awake male macaques. Among face-selective patches of the superior temporal sulcus (STS), we found a double dissociation of areas processing facial expression and those processing head orientation. The face-selective patches in the STS fundus were most sensitive to facial expression, as was the amygdala, whereas those on the lower, lateral edge of the sulcus were most sensitive to head orientation. The results of this study reveal a new dimension of functional organization, with face-selective patches segregating within the STS. The findings thus force a rethinking of the role of the face-processing system in representing subject-directed actions and supporting social cognition. SIGNIFICANCE STATEMENT When we are interacting ...

Alzheimer's disease (AD) is the leading cause of late-onset dementia, and there exists an unmet medical need for effective treatments for AD. The accumulation of neurotoxic amyloid-β (Aβ) plaques contributes to the pathophysiology of AD. EPHX2 encoding soluble epoxide hydrolase (sEH)—a key enzyme for epoxyeicosatrienoic acid (EET) signaling that is mainly expressed in lysosomes of astrocytes in the adult brain—is cosited at a locus associated with AD, but it is unclear whether and how it contributes to the pathophysiology of AD. In this report, we show that the pharmacologic inhibition of sEH with 1-trifluoromethoxyphenyl- 3-(1-propionylpiperidin-4-yl) urea (TPPU) or the genetic deletion of Ephx2 reduces Aβ deposition in the brains of both male and female familial Alzheimer's disease (5×FAD) model mice. The inhibition of sEH with TPPU or the genetic deletion of Ephx2 alleviated cognitive deficits and prevented astrocyte reactivation in the brains of 6-month-old male 5×FAD mice. 14,15-EET levels in the brai...