Allometric rules for mammalian cortical layer 5 neuron biophysics.

The biophysical properties of neurons are the foundation for computation in the brain. Neuronal size is a key determinant of single neuron input-output features and varies substantially across species1-3. However, it is unknown whether different species adapt neuronal properties to conserve how single neurons process information4-7. Here we characterize layer 5 cortical pyramidal neurons across 10 mammalian species to identify the allometric relationships that govern how neuronal biophysics change with cell size. In 9 of the 10 species, we observe conserved rules that control the conductance of voltage-gated potassium and HCN channels. Species with larger neurons, and therefore a decreased surface-to-volume ratio, exhibit higher membrane ionic conductances. This relationship produces a conserved conductance per unit brain volume. These size-dependent rules result in large but predictable changes in somatic and dendritic integrative properties. Human neurons do not follow these allometric relationships, exhibiting much lower voltage-gated potassium and HCN conductances. Together, our results in layer 5 neurons identify conserved evolutionary principles for neuronal biophysics in mammals as well as notable features of the human cortex.

TACAN Is an Ion Channel Involved in Sensing Mechanical Pain.

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Although the mechanisms for some of these functions have been identified, the molecules essential to the sense of pain have remained elusive. Here we report identification of TACAN (Tmem120A), an ion channel involved in sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. Finally, a nociceptor-specific inducible knockout of TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to painful mechanical stimuli but not to thermal or touch stimuli. We propose that TACAN is an ion channel that contributes to sensing mechanical pain.

Widespread and Highly Correlated Somato-dendritic Activity in Cortical Layer 5 Neurons.

Dendritic integration can expand the information-processing capabilities of neurons. However, the recruitment of active dendritic processing in vivo and its relationship to somatic activity remain poorly understood. Here, we use two-photon GCaMP6f imaging to simultaneously monitor dendritic and somatic compartments in the awake primary visual cortex. Activity in layer 5 pyramidal neuron somata and distal apical trunk dendrites shows surprisingly high functional correlation. This strong coupling persists across neural activity levels and is unchanged by visual stimuli and locomotion. Ex vivo combined somato-dendritic patch-clamp and GCaMP6f recordings indicate that dendritic signals specifically reflect local electrogenesis triggered by dendritic inputs or high-frequency bursts of somatic action potentials. In contrast to the view that dendrites are only sparsely recruited under highly specific conditions in vivo, our results provide evidence that active dendritic integration is a widespread and intrinsic feature of cortical computation.

Enhanced Dendritic Compartmentalization in Human Cortical Neurons.

The biophysical features of neurons shape information processing in the brain. Cortical neurons are larger in humans than in other species, but it is unclear how their size affects synaptic integration. Here, we perform direct electrical recordings from human dendrites and report enhanced electrical compartmentalization in layer 5 pyramidal neurons. Compared to rat dendrites, distal human dendrites provide limited excitation to the soma, even in the presence of dendritic spikes. Human somas also exhibit less bursting due to reduced recruitment of dendritic electrogenesis. Finally, we find that decreased ion channel densities result in higher input resistance and underlie the lower coupling of human dendrites. We conclude that the increased length of human neurons alters their input-output properties, which will impact cortical computation. VIDEO ABSTRACT.

Dendritic Spines Prevent Synaptic Voltage Clamp.

Synapses are the fundamental units of information processing in the mammalian brain. Much of our understanding of their functional properties comes from voltage-clamp analysis, the predominant approach for investigating synaptic physiology. Here, we reveal that voltage clamp is completely ineffective for most excitatory synapses due to spine electrical compartmentalization. Under local dendritic voltage clamp, single-spine activation produced large spine head depolarizations that severely distorted measurements and recruited voltage-dependent channels. To overcome these voltage-clamp errors, we developed an approach to provide new, accurate measurements of synaptic conductance. Single-synapse AMPA conductance was much larger than previously appreciated, producing saturation effects on synaptic currents. We conclude that electrical compartmentalization profoundly shapes both synaptic function and how that function can be assessed with electrophysiological methods.

Enhancing circadian clock function in cancer cells inhibits tumor growth.

BACKGROUND: Circadian clocks control cell cycle factors, and circadian disruption promotes cancer. To address whether enhancing circadian rhythmicity in tumor cells affects cell cycle progression and reduces proliferation, we compared growth and cell cycle events of B16 melanoma cells and tumors with either a functional or dysfunctional clock. RESULTS: We found that clock genes were suppressed in B16 cells and tumors, but treatments inducing circadian rhythmicity, such as dexamethasone, forskolin and heat shock, triggered rhythmic clock and cell cycle gene expression, which resulted in fewer cells in S phase and more in G1 phase. Accordingly, B16 proliferation in vitro and tumor growth in vivo was slowed down. Similar effects were observed in human colon carcinoma HCT-116 cells. Notably, the effects of dexamethasone were not due to an increase in apoptosis nor to an enhancement of immune cell recruitment to the tumor. Knocking down the essential clock gene Bmal1 in B16 tumors prevented the effects of dexamethasone on tumor growth and cell cycle events. CONCLUSIONS: Here we demonstrated that the effects of dexamethasone on cell cycle and tumor growth are mediated by the tumor-intrinsic circadian clock. Thus, our work reveals that enhancing circadian clock function might represent a novel strategy to control cancer progression.