Breathing control center neurons that promote arousal in mice.

Slow, controlled breathing has been used for centuries to promote mental calming, and it is used clinically to suppress excessive arousal such as panic attacks. However, the physiological and neural basis of the relationship between breathing and higher-order brain activity is unknown. We found a neuronal subpopulation in the mouse preBötzinger complex (preBötC), the primary breathing rhythm generator, which regulates the balance between calm and arousal behaviors. Conditional, bilateral genetic ablation of the ~175 Cdh9/Dbx1 double-positive preBötC neurons in adult mice left breathing intact but increased calm behaviors and decreased time in aroused states. These neurons project to, synapse on, and positively regulate noradrenergic neurons in the locus coeruleus, a brain center implicated in attention, arousal, and panic that projects throughout the brain.

Regulation of Thalamic and Cortical Network Synchrony by Scn8a.

Voltage-gated sodium channel (VGSC) mutations cause severe epilepsies marked by intermittent, pathological hypersynchronous brain states. Here we present two mechanisms that help to explain how mutations in one VGSC gene, Scn8a, contribute to two distinct seizure phenotypes: (1) hypoexcitation of cortical circuits leading to convulsive seizure resistance, and (2) hyperexcitation of thalamocortical circuits leading to non-convulsive absence epilepsy. We found that loss of Scn8a leads to altered RT cell intrinsic excitability and a failure in recurrent RT synaptic inhibition. We propose that these deficits cooperate to enhance thalamocortical network synchrony and generate pathological oscillations. To our knowledge, this finding is the first clear demonstration of a pathological state tied to disruption of the RT-RT synapse. Our observation that loss of a single gene in the thalamus of an adult wild-type animal is sufficient to cause spike-wave discharges is striking and represents an example of absence epilepsy of thalamic origin.

Bidirectional Control of Generalized Epilepsy Networks via Rapid Real-Time Switching of Firing Mode.

Thalamic relay neurons have well-characterized dual firing modes: bursting and tonic spiking. Studies in brain slices have led to a model in which rhythmic synchronized spiking (phasic firing) in a population of relay neurons leads to hyper-synchronous oscillatory cortico-thalamo-cortical rhythms that result in absence seizures. This model suggests that blocking thalamocortical phasic firing would treat absence seizures. However, recent in vivo studies in anesthetized animals have questioned this simple model. Here we resolve this issue by developing a real-time, mode-switching approach to drive thalamocortical neurons into or out of a phasic firing mode in two freely behaving genetic rodent models of absence epilepsy. Toggling between phasic and tonic firing in thalamocortical neurons launched and aborted absence seizures, respectively. Thus, a synchronous thalamocortical phasic firing state is required for absence seizures, and switching to tonic firing rapidly halts absences. This approach should be useful for modulating other networks that have mode-dependent behaviors.

Brain-Wide Maps of Synaptic Input to Cortical Interneurons.

Cortical inhibition is mediated by diverse inhibitory neuron types that can each play distinct roles in information processing by virtue of differences in their input sources, intrinsic properties, and innervation targets. Previous studies in brain slices have demonstrated considerable cell-type specificity in laminar sources of local inputs. In contrast, little is known about possible differences in distant inputs to different cortical interneuron types. We used the monosynaptic rabies virus system, in conjunction with mice expressing Cre recombinase in either parvalbumin-positive, somatostatin-positive (SST+), or vasoactive intestinal peptide-positive (VIP+) neurons, to map the brain-wide input to the three major nonoverlapping classes of interneurons in mouse somatosensory cortex. We discovered that all three classes of interneurons received considerable input from known cortical and thalamic input sources, as well as from probable cholinergic cells in the basal nucleus of Meynert. Despite their common input sources, these classes differed in the proportion of long-distance cortical inputs originating from deep versus superficial layers. Similar to their laminar differences in local input, VIP+ neurons received inputs predominantly from deep layers while SST+ neurons received mostly superficial inputs. These classes also differed in the amount of input they received. Cortical and thalamic inputs were greatest onto VIP+ interneurons and smallest onto SST+ neurons. SIGNIFICANCE STATEMENT: These results indicate that all three major interneuron classes in the barrel cortex integrate both feedforward and feedback information from throughout the brain to modulate the activity of the local cortical circuit. However, differences in laminar sources and magnitude of distant cortical input suggest differential contributions from cortical areas. More input to vasoactive intestinal peptide-positive (VIP+) neurons than to somatostatin-positive (SST+) neurons suggests that disinhibition of the cortex via VIP+ cells, which inhibit SST+ cells, might be a general feature of long-distance corticocortical and thalamocortical circuits.

Absence seizure susceptibility correlates with pre-ictal ß oscillations.

Absence seizures are generalized, cortico-thalamo-cortical (CTC) high power electroencephalographic (EEG) or electrocorticographic (ECoG) events that initiate and terminate suddenly. ECoG recordings of absence seizures in animal models of genetic absence epilepsy show a sudden spike-wave-discharge (SWD) onset that rapidly emerges from normal ECoG activity. However, given that absence seizures occur most often during periods of drowsiness or quiet wakefulness, we wondered whether SWD onset correlates with pre-ictal changes in network activity. To address this, we analyzed ECoG recordings of both spontaneous and induced SWDs in rats with genetic absence epilepsy. We discovered that the duration and intensity of spontaneous SWDs positively correlate with pre-ictal 20-40Hz (ß) spectral power and negatively correlate with 4-7Hz (Ø) power. In addition, the output of thalamocortical neurons decreases within the same pre-ictal window of time. In separate experiments we found that the propensity for SWD induction was correlated with pre-ictal ß power. These results argue that CTC networks undergo a pre-seizure state transition, possibly due to a functional reorganization of cortical microcircuits, which leads to the generation of absence seizures.

Adverse functional effects of chemotherapy on whole-brain metabolism: a PET/CT quantitative analysis of FDG metabolic pattern of the "chemo-brain".

PURPOSE: With its unique ability to assess function through metabolism, FDG PET may provide key insight into the adverse effects of chemotherapy on the brain by shedding light on its cognitive and psychological consequences, a well-known phenomenon in cancer patients who undergo such treatments. PATIENTS AND METHODS: Twenty-one patients with untreated non-Hodgkin lymphoma and no involvement of the central nervous system were selected from an existing database for this investigation. An adaptive threshold imaging software called ROVER was used to analyze and quantify FDG PET scans for assessing whole-brain metabolism. A 3D spherical region of interest was drawn surrounding the cerebral cortex, excluding subcortical and non-cortical areas. RESULTS: We noted a mean reduction of 1308.86 ± 394.74 SUV-cc (P = 0.03) in the whole-brain cortical glycolysis after standard chemotherapy, which translated to a decrease of 16.9 ± 5.04% (P = 0.03) in the measured structures. CONCLUSION: These results demonstrate the potential role of such adaptive quantitative techniques in studying underlying biological effects of chemotherapy and offer a promising avenue for future research in this field.