Laminar evoked responses in mouse somatosensory cortex suggest a special role for deep layers in cortical complexity.

It has been suggested that consciousness is closely related to the complexity of the brain. The perturbational complexity index (PCI) has been used in humans and rodents to distinguish conscious from unconscious states based on the global cortical responses (recorded by electroencephalography, EEG) to local cortical stimulation (CS). However, it is unclear how different cortical layers respond to CS and contribute to the resulting intra- and inter-areal cortical connectivity and PCI. A detailed investigation of the local dynamics is needed to understand the basis for PCI. We hypothesized that the complexity level of global cortical responses (PCI) correlates with layer-specific activity and connectivity. We tested this idea by measuring global cortical dynamics and layer-specific activity in the somatosensory cortex (S1) of mice, combining cortical electrical stimulation in deep motor cortex, global electrocorticography (ECoG) and local laminar recordings from layers 1-6 in S1, during wakefulness and general anaesthesia (sevoflurane). We found that the transition from wake to sevoflurane anaesthesia correlated with a drop in both the global and local PCI (PCIst ) values (complexity). This was accompanied by a local decrease in neural firing rate, spike-field coherence and long-range functional connectivity specific to deep layers (L5, L6). Our results suggest that deep cortical layers are mechanistically important for changes in PCI and thereby for changes in the state of consciousness.

Kisspeptin modulates sexual and emotional brain processing in humans.

BACKGROUND: Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behavior. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviors, and is a likely candidate system for the integration of behavior with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behavior. METHODS: Using a combination of functional neuroimaging and hormonal and psychometric analyses, we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men. RESULTS: We demonstrated that kisspeptin administration enhanced limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin's enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance. In addition, kisspeptin administration attenuated negative mood. CONCLUSIONS: Collectively, our data provide evidence of an undescribed role for kisspeptin in integrating sexual and emotional brain processing with reproduction in humans. These results have important implications for our understanding of reproductive biology and are highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function. FUNDING: National Institute for Health Research (NIHR), Wellcome Trust (Ref 080268), and the Medical Research Council (MRC).

Physiological roles of Kv2 channels in entorhinal cortex layer II stellate cells revealed by Guangxitoxin-1E.

KEY POINTS: Kv2 channels underlie delayed-rectifier potassium currents in various neurons, although their physiological roles often remain elusive. Almost nothing is known about Kv2 channel functions in medial entorhinal cortex (mEC) neurons, which are involved in representing space, memory formation, epilepsy and dementia. Stellate cells in layer II of the mEC project to the hippocampus and are considered to be space-representing grid cells. We used the new Kv2 blocker Guangxitoxin-1E (GTx) to study Kv2 functions in these neurons. Voltage clamp recordings from mEC stellate cells in rat brain slices showed that GTx inhibited delayed-rectifier K+ current but not transient A-type current. In current clamp, GTx had multiple effects: (i) increasing excitability and bursting at moderate spike rates but reducing firing at high rates; (ii) enhancing after-depolarizations; (iii) reducing the fast and medium after-hyperpolarizations; (iv) broadening action potentials; and (v) reducing spike clustering. GTx is a useful tool for studying Kv2 channels and their functions in neurons. ABSTRACT: The medial entorhinal cortex (mEC) is strongly involved in spatial navigation, memory, dementia and epilepsy. Although potassium channels shape neuronal activity, their roles in mEC are largely unknown. We used the new Kv2 blocker Guangxitoxin-1E (GTx; 10-100 nm) in rat brain slices to investigate Kv2 channel functions in mEC layer II stellate cells (SCs). These neurons project to the hippocampus and are considered to be grid cells representing space. Voltage clamp recordings from SCs nucleated patches showed that GTx inhibited a delayed rectifier K+ current activating beyond -30 mV but not transient A-type current. In current clamp, GTx (i) had almost no effect on the first action potential but markedly slowed repolarization of late spikes during repetitive firing; (ii) enhanced the after-depolarization (ADP); (iii) reduced fast and medium after-hyperpolarizations (AHPs); (iv) strongly enhanced burst firing and increased excitability at moderate spike rates but reduced spiking at high rates; and (v) reduced spike clustering and rebound potentials. The changes in bursting and excitability were related to the altered ADPs and AHPs. Kv2 channels strongly shape the activity of mEC SCs by affecting spike repolarization, after-potentials, excitability and spike patterns. GTx is a useful tool and may serve to further clarify Kv2 channel functions in neurons. We conclude that Kv2 channels in mEC SCs are important determinants of intrinsic properties that allow these neurons to produce spatial representation. The results of the present study may also be important for the accurate modelling of grid cells.

IK1 channels do not contribute to the slow afterhyperpolarization in pyramidal neurons.

In pyramidal neurons such as hippocampal area CA1 and basolateral amygdala, a slow afterhyperpolarization (sAHP) follows a burst of action potentials, which is a powerful regulator of neuronal excitability. The sAHP amplitude increases with aging and may underlie age related memory decline. The sAHP is due to a Ca(2+)-dependent, voltage-independent K(+) conductance, the molecular identity of which has remained elusive until a recent report suggested the Ca(2+)-activated K(+) channel, IK1 (KCNN4) as the sAHP channel in CA1 pyramidal neurons. The signature pharmacology of IK1, blockade by TRAM-34, was reported for the sAHP and underlying current. We have examined the sAHP and find no evidence that TRAM-34 affects either the current underling the sAHP or excitability of CA1 or basolateral amygdala pyramidal neurons. In addition, CA1 pyramidal neurons from IK1 null mice exhibit a characteristic sAHP current. Our results indicate that IK1 channels do not mediate the sAHP in pyramidal neurons.

Dorsoventral differences in Kv7/M-current and its impact on resonance, temporal summation and excitability in rat hippocampal pyramidal cells.

In rodent hippocampi, the connections, gene expression and functions differ along the dorsoventral (D-V) axis. CA1 pyramidal cells show increasing excitability along the D-V axis, although the underlying mechanism is not known. In the present study, we investigated how the M-current (IM ), caused by Kv7/M (KCNQ) potassium channels, and known to often control neuronal excitability, contributes to D-V differences in intrinsic properties of CA1 pyramidal cells. Using whole-cell patch clamp recordings and the selective Kv7/M blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE991) in hippocampal slices from 3- to 4-week-old rats, we found that: (i) IM had a stronger impact on subthreshold electrical properties in dorsal than ventral CA1 pyramidal cells, including input resistance, temporal summation of artificial synaptic potentials, and M-resonance; (ii) IM activated at more negative potentials (left-shifted) and had larger peak amplitude in the dorsal than ventral CA1; and (iii) the initial spike threshold (during ramp depolarizations) was elevated, and the medium after-hyperpolarization and spike frequency adaptation were increased (i.e. excitability was lower) in the dorsal rather than ventral CA1. These differences were abolished or reduced by application of XE991, indicating that they were caused by IM . Thus, it appears that IM has stronger effects in dorsal than in ventral rat CA1 pyramidal cells because of a larger maximal M-conductance and left-shifted activation curve in the dorsal cells. These mechanisms may contribute to D-V differences in the rate and phase coding of position by CA1 place cells, and may also enhance epileptiform activity in ventral CA1.

Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-α and IL-1ß is mediated by glial cells.

Long-term potentiation (LTP) of synaptic strength in nociceptive pathways is a cellular model of hyperalgesia. The emerging literature suggests a role for cytokines released by spinal glial cells for both LTP and hyperalgesia. However, the underlying mechanisms are still not fully understood. In rat lumbar spinal cord slices, we now demonstrate that conditioning high-frequency stimulation of primary afferents activated spinal microglia within <30 min and spinal astrocytes within ~2 s. Activation of spinal glia was indispensible for LTP induction at C-fiber synapses with spinal lamina I neurons. The cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), which are both released by activated glial cells, were individually sufficient and necessary for LTP induction via redundant pathways. They differentially amplified 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propanoic acid receptor-mediated and N-methyl-D-aspartic acid receptor-mediated synaptic currents in lamina I neurons. Unexpectedly, the synaptic effects by IL-1ß and TNF-α were not mediated directly via activation of neuronal cytokine receptors, but rather, indirectly via IL-1 receptors and TNF receptors being expressed on glial cells in superficial spinal dorsal horn. Bath application of IL-1ß or TNF-α led to the release profiles of pro-inflammatory and anti-inflammatory cytokines, chemokines, and growth factors, which overlapped only partially. Heat hyperalgesia induced by spinal application of either IL-1ß or TNF-α in naive animals also required activation of spinal glial cells. These results reveal a novel, decisive role of spinal glial cells for the synaptic effects of IL-1ß and TNF-α and for some forms of hyperalgesia.