Journal of Neuroscience

Many aspects of brain processing are intimately linked to brain rhythms. Essentially all classical brain rhythms, i.e., delta, theta, alpha, beta, and sleep waves, are highly heritable. This renders brain rhythms an interesting intermediate phenotype for cognitive and behavioral traits. One brain rhythm that has been particularly strongly linked to cognition is the gamma rhythm: it is involved in attention, short- and long-term memory, and conscious awareness. It has been described in sensory and motor cortices, association and control structures, and the hippocampus. In contrast to most other brain rhythms, the gamma frequency highly depends on stimulus and task conditions, suggesting a low heritability. However, the heritability of gamma has not been assessed. Here, we show that visually induced gamma-band synchronization in humans is strongly genetically determined. Eighty twin subjects (20 monozygotic and 20 dizygotic twin pairs) viewed a moving sinusoidal grating while their brain activity was recorded using magnetoencephalography. The stimulus induced spectrally confined gamma-band activity in sensors over visual cortex in all subjects, with individual peak frequencies ranging from 45 to 85 Hz. Gamma-band peak frequencies were highly correlated across monozygotic twins (r= 0.88), but not across dizygotic twins (r= 0.32) or unrelated subjects (r= 0.02). This implies a heritability of the gamma-band frequency of 91%. This strong genetic determination suggests that gamma-related cognitive functions are under close genetic control.

Mutations in Kinesin proteins (Kifs) are linked to various neurological diseases, but the specific and redundant functions of the vertebrate Kifs are incompletely understood. For example, Kif5A, but not other Kinesin-1 heavy-chain family members, is implicated in Charcot-Marie-Tooth disease (CMT) and Hereditary Spastic Paraplegia (HSP), but the mechanism of its involvement in the progressive axonal degeneration characteristic of these diseases is not well understood. We report that zebrafishkif5Aamutants exhibit hyperexcitability, peripheral polyneuropathy, and axonal degeneration reminiscent of CMT and HSP. Strikingly, althoughkif5genes are thought to act largely redundantly in other contexts, and zebrafish peripheral neurons express fivekif5genes,kif5Aamutant peripheral sensory axons lack mitochondria and degenerate. We show that this Kif5Aa-specific function is cell autonomous and is mediated by its C-terminal tail, as only Kif5Aa and chimeric motors containing the Kif5Aa C-tail can rescue deficits. Finally, concurrent loss of thekinesin-3,kif1b, or its adaptorkbp, exacerbates axonal degeneration via a nonmitochondrial cargo common to Kif5Aa. Our results shed light on Kinesin complexity and reveal determinants of specific Kif5A functions in mitochondrial transport, adaptor binding, and axonal maintenance.

Cells in injured and inflamed tissues produce a number of proalgesic lipid-derived mediators, which excite nociceptive neurons by activating selective G-protein-coupled receptors or ligand-gated ion channels. Recent work has shown that these proalgesic factors are counteracted by a distinct group of lipid molecules that lower nociceptor excitability and attenuate nociception in peripheral tissues. Analgesic lipid mediators include endogenous agonists of cannabinoid receptors (endocannabinoids), lipid-amide agonists of peroxisome proliferator-activated receptor-α, and products of oxidative metabolism of polyunsaturated fatty acids via cytochrome P₄₅₀and other enzyme pathways. Evidence indicates that these lipid messengers are produced and act at different stages of inflammation and the response to tissue injury, and may be part of a peripheral gating mechanism that regulates the access of nociceptive information to the spinal cord and the brain. Growing knowledge about this peripheral control system may be used to discover safer medicines for pain.

Ca²+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in synaptic plasticity and memory formation in a variety of learning systems and species. The present experiments examined the role of CaMKII in the circuitry underlying pavlovian fear conditioning. First, we reveal by immunocytochemical and tract-tracing methods that αCaMKII is postsynaptic to auditory thalamic inputs and colocalized with the NR2B subunit of the NMDA receptor. Furthermore, we show that fear conditioning results in an increase of the autophosphorylated (active) form of αCaMKII in lateral amygdala (LA) spines. Next, we demonstrate that intra-amygdala infusion of a CaMK inhibitor, 1-[NO-bis-1,5-isoquinolinesulfonyl]-N-methyl-l-tyrosyl-4-phenylpiperazine, KN-62, dose-dependently impairs the acquisition, but not the expression, of auditory and contextual fear conditioning. Finally, in electrophysiological experiments, we demonstrate that an NMDA receptor-dependent form of long-term potentiation at thalamic input synapses to the LA is impaired by bath application of KN-62in vitro. Together, the results of these experiments provide the first comprehensive view of the role of CaMKII in the amygdala during fear conditioning.

Dopaminergic amacrine cells were stained in cat, rat, and rabbit retina using an antibody against tyrosine hydroxylase (TH). Following intraocular injection of DAPI (4,6,diamidino-2-phenylindole), subsequent retinal whole-mount preparations revealed that the dopaminergic fiber plexus formed rings around amacrine cell bodies. Intracellular injection of Lucifer yellow (LY) into A II amacrine cells confirmed that this rod-related, bistratified interneuron has its cell body within the dopaminergic rings. Using a photooxidation process, LY was transformed into an electron-dense reaction product, enabling ultrastructural examination of LY-injected A II amacrine cells. In retinae counterstained with an antibody against TH, it was possible to show synapses from TH-positive fibers onto these cells. The dopaminergic plexus was further investigated by injecting single dopaminergic cells with LY and thus revealing their branching pattern. The present results emphasize the role of dopamine in modulating the rod pathway in mammalian retina.

Type I and type III Na+ channels are localized mainly in neuronal cell bodies in mouse brain. Type II channels are preferentially localized in unmyelinated fiber tracts but are not detectable in normally myelinated fibers. In shiverer mice, which lack compact myelin due to a defect in the myelin basic protein gene, elevated expression of type II Na+ channels was observed in the hypomyelinated axons of large-caliber fiber tracts such as the corpus callosum, internal capsule, fimbria, fornix, corpus medullare of the cerebellum, and nigrostriatal pathway by immunocytochemical analysis with subtype-specific antibodies. No difference was observed in the localization of type I and type III Na+ channels between wild-type and shiverer mice. These findings support the hypothesis that type II Na+ channels are preferentially localized in axons of brain neurons and suggest that their density and localization are regulated by myelination. The selective increase in the number of type II channels in hypomyelinated fiber tracts may contribute to the hyperexcitable phenotype of the shiverer mouse.

Granule cells are axonless local interneurons that mediate lateral inhibitory interactions between the principal neurons of the olfactory bulb via dendrodendritic reciprocal synapses. This unusual arrangement may give rise to functional properties different from conventional lateral inhibition. Although granule cells spike, little is known about the role of the action potential with respect to their synaptic output. To investigate the signals that underlie dendritic release in these cells, two-photon microscopy in rat brain slices was used to image calcium transients in granule cell dendrites and spines. Action potentials evoked calcium transients throughout the dendrites, with amplitudes increasing with distance from soma and attaining a plateau level within the external plexiform layer, the zone of granule cell synaptic output. Transient amplitudes were, on average, equal in size in spines and adjacent dendrites. Surprisingly, both spine and dendritic amplitudes were strongly dependent on membrane potential, decreasing with depolarization and increasing with hyperpolarization from rest. Both the current-voltage relationship and the time course of inactivation were consistent with the known properties of T-type calcium channels, and the voltage dependence was blocked by application of the T-type calcium channel antagonists Ni²⁺and mibefradil. In addition, mibefradil reduced action potential-mediated synaptic transmission from granule to mitral cells. The implication of a transiently inactivating calcium channel in synaptic release from granule cells suggests novel mechanisms for the regulation of lateral inhibition in the olfactory bulb.

Neocortical neuronal activity is characterized by complex spatiotemporal dynamics. Although slow oscillations have been shown to travel over space in terms of consistent phase advances, it is unknown how this phenomenon relates to neuronal activity in other frequency bands. We here present electrocorticographic data from three male and one female human subject and demonstrate that gamma power is phase locked to traveling alpha waves. Given that alpha activity has been proposed to coordinate neuronal processing reflected in the gamma band, we suggest that alpha waves are involved in coordinating neuronal processing in both space and time.

We found a protein in Aplysia neurons that has many characteristics of the transcription factor NF-κB. Thus, the protein recognized a radiolabeled probe containing the κB sequence from the human interferon-β gene enhancer element (PRDII), and the binding was not affected by PRDIV, an ATF-2 enhancer sequence from the same gene. Binding was efficiently inhibited, however, by nonradioactive oligonucleotides containing H2, the κB site from the major histocompatibility complex I gene promotor. In addition, recombinant mammalian IκB-α, which associates specifically with the P65 subunit of NF-κB, inhibited the binding to the PRDII probe in a dose-dependent manner. The nuclear form of the Aplysia protein was constitutively active. Axoplasm, however, contained the constitutively active form as well as a latent form. The latter was activated by treatment with deoxycholate under the same conditions as mammalian NF-κB. Based on these findings, we believe the protein to be a homolog of NF-κB. To investigate the role of apNF-κB in the axon, we crushed the peripheral nerves to the body wall. Surprisingly, there was a rapid loss of apNF-κB binding at the crush site and, within 15 min, as far as 2.5 cm along the axon. In contrast, exposing either the intact animal or the nervous systemin situto levels of 5-HT that induce synaptic facilitation did not affect apNF-κB activity.