•Adult neurogenesis increases orienting toward a novel stimulus during focused activity.•Rats without ongoing neurogenesis orient normally when they are exploring.•Four-week-old neurons affect ...orienting behavior, but younger neurons do not.•Changes in refocusing of attention, or distraction, could affect memory tasks.
New granule neurons are born in the dentate gyrus region of the hippocampus throughout life. Behavioral effects of slowing or stopping this ongoing neurogenesis are generally observed only in complex cognitive tasks involving high levels of cue or memory interference or in tests of emotion presented after stress exposure. Here, we tested the role of new neurons in naïve rats in a simple, one-trial orienting task previously shown to be affected by hippocampal lesions. Using a pharmacogenetic method to inhibit adult neurogenesis, we found that loss of new neurons decreased orienting toward a novel auditory cue. Rats lacking new neurons showed this change in orienting only when they were drinking from a water bottle and not when they were exploring an empty arena, suggesting that the deficit is not in the ability to orient to a novel sound but in shifting of attention toward a second stimulus. Orienting was reduced to the same extent after 4 or 8 weeks of neurogenesis reduction but was not detectably altered after 2 or 3 weeks of treatment, suggesting that new neurons must mature for approximately a month before functioning in this behavior. These findings demonstrate that adult-born neurons affect behavior in a simple attention reorienting task in naïve animals with no prior stress or task-related learning.
BORC is a multisubunit complex previously shown to promote coupling of mammalian lysosomes and C. elegans synaptic vesicle (SV) precursors (SVPs) to kinesins for anterograde transport of these ...organelles along microtubule tracks. We attempted to meld these observations into a unified model for axonal transport in mammalian neurons by testing two alternative hypotheses: (1) that SV and lysosomal proteins are co-transported within a single type of “lysosome-related vesicle” and (2) that SVPs and lysosomes are distinct organelles, but both depend on BORC for axonal transport. Analyses of various types of neurons from wild-type rats and mice, as well as from BORC-deficient mice, show that neither hypothesis is correct. We find that SVPs and lysosomes are transported separately, but only lysosomes depend on BORC for axonal transport in these neurons. These findings demonstrate that SVPs and lysosomes are distinct organelles that rely on different machineries for axonal transport in mammalian neurons.
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•Lysosomes and synaptic vesicle precursors (SVPs) move separately in mammalian axons•BORC is required for transport of lysosomes but not SVPs in mammalian axons•BORC-subunit knockout causes axon swellings and neonatal death in mice•Defective axonal lysosome transport may underlie pathology of human BORC deficiency
De Pace et al. show that lysosomes and synaptic vesicle precursors (SVPs) are distinct organelles that move separately from the soma to the axon in rat and mouse neurons. Moreover, they demonstrate that the BLOC-1-related complex (BORC) is required for the transport of lysosomes but not SVPs in mouse neurons.
The hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of disorders characterized by progressive lower limb spasticity. Mutations in subunits of the ...heterotetrameric (ε-β4-μ4-σ4) adaptor protein 4 (AP-4) complex cause an autosomal recessive form of complicated HSP referred to as "AP-4 deficiency syndrome". In addition to lower limb spasticity, this syndrome features intellectual disability, microcephaly, seizures, thin corpus callosum and upper limb spasticity. The pathogenetic mechanism, however, remains poorly understood. Here we report the characterization of a knockout (KO) mouse for the AP4E1 gene encoding the ε subunit of AP-4. We find that AP-4 ε KO mice exhibit a range of neurological phenotypes, including hindlimb clasping, decreased motor coordination and weak grip strength. In addition, AP-4 ε KO mice display a thin corpus callosum and axonal swellings in various areas of the brain and spinal cord. Immunohistochemical analyses show that the transmembrane autophagy-related protein 9A (ATG9A) is more concentrated in the trans-Golgi network (TGN) and depleted from the peripheral cytoplasm both in skin fibroblasts from patients with mutations in the μ4 subunit of AP-4 and in various neuronal types in AP-4 ε KO mice. ATG9A mislocalization is associated with increased tendency to accumulate mutant huntingtin (HTT) aggregates in the axons of AP-4 ε KO neurons. These findings indicate that the AP-4 ε KO mouse is a suitable animal model for AP-4 deficiency syndrome, and that defective mobilization of ATG9A from the TGN and impaired autophagic degradation of protein aggregates might contribute to neuroaxonal dystrophy in this disorder.
Cognitive reserve (CR) is a protective mechanism that supports sustained cognitive function following damage to the physical brain associated with age, injury, or disease. The goal of the research ...was to identify relationships between age, CR, and brain connectivity. A sample of 90 cognitively normal adults, ages 45-64 years, had their resting-state brain activity recorded with electroencephalography (EEG) and completed a series of memory and executive function assessments. CR was estimated using years of education and verbal IQ scores. Participants were divided into younger and older age groups and low- and high-CR groups. We observed greater left- than right-hemisphere coherence in younger participants, and greater right- than left-hemisphere coherence in older participants. In addition, greater coherence was observed under eyes-closed than eyes-open recording conditions for both low-CR and high-CR participants, with a more substantial difference between recording conditions in individuals high in CR regardless of age. Finally, younger participants low in CR exhibited greater mean coherence than younger participants high in CR, whereas the opposite pattern was observed in older participants, with greater coherence in older participants high in CR. Together, these findings suggest the possibility of a shift in the relationship between CR and brain connectivity during aging.
Isolated injury to the radial or ulnar artery results in no significant complications in patients who undergo repair or ligation of the injured artery. However, ligation of both infrabrachial vessels ...of the upper extremity is associated with limb loss from ischemia due to lack of collateral circulation. A rare case of acute ligation of both the radial and ulnar arteries in a drug abuser where collateral vessels preserved the circulation to the hand is reported.
Acute compression of the median nerve in the forearm usually occurs from compartment syndrome. A case of acute compression neuropathy of the median nerve from a foreign body, where there was no ...evidence of compartment syndrome, is reported. The diagnosis was made from the patient's symptoms and radiographs. Early recognition and decompression of the forearm with removal of the foreign body led to full recovery.
To test the hypothesis that induction of BDNF may contribute to changes in hippocampal excitability occurring during the female reproductive cycle, we examined the distribution of BDNF ...immunoreactivity and changes in CA1 and CA3 electrophysiology across the estrous cycle in rats. Hippocampal BDNF immunoreactivity increased on the day of proestrus as well as on the following morning (estrus), relative to metestrus or ovariectomized animals. Changes in immunoreactivity were clearest in mossy fiber axons of dentate gyrus granule cells, which contain the highest concentration of BDNF. Increased immunoreactivity was also apparent in the neuropil-containing dendrites of CA1 and CA3 neurons. Electrophysiological recordings in hippocampal slices showed robust cycle-dependent differences. Evoked responses of CA1 neurons to Schaffer collateral stimulation changed over the cycle, with larger maximum responses at both proestrus and estrus relative to metestrus. In area CA3, repetitive hilar stimuli frequently evoked multiple population spikes at proestrus and estrus but only rarely at other cycle stages, and never in slices of ovariectomized rats. Hyperexcitability in area CA3 at proestrus was blocked by exposure to the high-affinity neurotrophin receptor antagonist K252a, or an antagonist of the alpha7 nicotinic cholinergic receptor, whereas it was induced at metestrus by the addition of BDNF to hippocampal slices. These studies suggest that hippocampal BDNF levels change across the estrous cycle, accompanied by neurophysiological responses that resemble the effects of BDNF treatment. An estrogen-induced interaction of BDNF and alpha7 nicotinic receptors on mossy fibers seems responsible for estrous cycle changes in area CA3. Periovulatory changes in hippocampal function may, thus, involve estrogen-induced increases in BDNF expression.
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