Assessment of Executive and Cognitive Functions in Children with Restless Sleep Disorder: A Pilot Study.

Restless sleep disorder affects children and is characterized by frequent nocturnal movements, iron deficiency, and daytime symptoms such as poor school performance or behavioral problems. Although sleep parameters have been thoroughly studied and daytime sleepiness has been previously assessed, neurocognitive and executive functions have not. In this study, we evaluated neurocognitive functions in a group of 13 children diagnosed with restless sleep disorder using the National Institute of Health Toolbox (NIH toolbox). The mean age was 10.62 (S.D. 2.785). Among them, seven were male and six were female. The fully corrected T-scores (adjusted for demographic variables: age, ethnicity, and education level) showed the lowest values for the Flanker test (selective attention) and dimensional change card sorting test (cognitive flexibility and inhibitory control), with a very large effect size vs. the corresponding expected frequencies. For all the other tests, the average scores were 50; however, individual children scored low on pattern recognition and two composite scores (fluid and total). In conclusion, these data support the fact that cognitive functions are affected in children with restless sleep disorder, especially selective attention. Clinicians must recognize sleep disorders and daytime impairment in order to promptly intervene and prevent cognitive impairments.

Circuits That Mediate Expression of Signaled Active Avoidance Converge in the Pedunculopontine Tegmentum.

An innocuous sensory stimulus that reliably signals an upcoming aversive event can be conditioned to elicit locomotion to a safe location before the aversive outcome ensues. The neural circuits that mediate the expression of this signaled locomotor action, known as signaled active avoidance, have not been identified. While exploring sensorimotor midbrain circuits in mice of either sex, we found that excitation of GABAergic cells in the substantia nigra pars reticulata blocks signaled active avoidance by inhibiting cells in the pedunculopontine tegmental nucleus (PPT), not by inhibiting cells in the superior colliculus or thalamus. Direct inhibition of putative-glutamatergic PPT cells, excitation of GABAergic PPT cells, or excitation of GABAergic afferents in PPT, abolish signaled active avoidance. Conversely, excitation of putative-glutamatergic PPT cells, or inhibition of GABAergic PPT cells, can be tuned to drive avoidance responses. The PPT is an essential junction for the expression of signaled active avoidance gated by nigral and other synaptic afferents.SIGNIFICANCE STATEMENT When a harmful situation is signaled by a sensory stimulus (e.g., street light), subjects typically learn to respond with active or passive avoidance responses that circumvent the threat. During signaled active avoidance behavior, subjects move away to avoid a threat signaled by a preceding innocuous stimulus. We identified a part of the midbrain essential to process the signal and avoid the threat. Inhibition of neurons in this area eliminates avoidance responses to the signal but preserves escape responses caused by presentation of the threat. The results highlight an essential part of the neural circuits that mediate signaled active avoidance behavior.

Basal Ganglia Output Controls Active Avoidance Behavior.

Engrained avoidance behavior is highly adaptive when it keeps away harmful events and can be highly maladaptive when individuals elude harmless situations in anxiety disorders, but the neural circuits that mediate avoidance are poorly understood. Using DREADDs and optogenetics in mice, we show that the output of the basal ganglia through the substantia nigra pars reticulata (SNr) controls active avoidance. SNr excitation blocks avoidance to a conditioned sensory stimulus while preserving the ability to escape the harmful event. Conversely, SNr inhibition facilitates avoidance to the conditioned stimulus and suffices to drive avoidance without any conditioned sensory stimulus. The results highlight a midbrain circuit that gates avoidance responses, which can be targeted to ameliorate maladaptive avoidance in psychiatric disorders. SIGNIFICANCE STATEMENT: In many circumstances, subjects respond to fearful situations with avoidance. This is a useful coping strategy in situations in which there is impending danger. However, avoidance responses can also be maladaptive, as in anxiety disorders such as phobias (e.g., avoiding air transportation) and social anxiety (e.g., avoiding social situations). Despite the obvious clinical relevance, little is known about the neural circuits that mediate active avoidance. Using chemogenetics and optogenetics, we show that the output of the basal ganglia fully controls active avoidance behavior.

Efecto de las crisis epilépticas parciales y generalizadas sobre la arquitectura del sueño en ratas / Effect of partial and generalised epileptic seizures on sleep architecture in rats

Introducción. La alteración del sueño producido por las crisis epilépticas se conoce; sin embargo, aún se tiene poca información de la alteración en el sueño por el tipo de crisis epiléptica. Materiales y métodos. Se evaluó la arquitectura del sueño de ratas en registros polisomnográficos de 36 horas tras inducirles crisis epilépticas parciales y generalizadas. Para la inducción de las crisis epilépticas se aplicaron in situ 50-100 UI de penicilina G sódica en la amígdala del lóbulo temporal. Resultados. Las crisis parciales y generalizadas provocaron el aumento en la latencia del sueño de ondas lentas (SOL) y sueño de movimiento oculares rápidos (MOR). El número de episodios de las fases de vigilia, SOL y sueño MOR disminuyó y la duración media de los episodios de la vigilia y del SOL aumentó, mientras que la del sueño MOR disminuyó. El porcentaje total del sueño MOR disminuyó significativamente. Durante el primer período de luz, las crisis parciales y generalizadas provocaron el incremento de la vigilia y la reducción de las fases del SOL y sueño MOR. En el período de oscuridad, aumentó el SOL, disminuyó la vigilia y no hubo cambios en el sueño MOR. En el segundo período de luz los porcentajes de las fases de vigilia y SOL regresaron a los valores control y el porcentaje del sueño MOR continuó disminuido. Conclusión. Los cambios en la organización del sueño dependen del tipo de crisis epiléptica que se presenta. Las crisis epilépticas generalizadas provocaron mayor deterioro en el sueño MOR (AU)

Introduction. It is a well-known fact that epileptic seizures disrupt sleep, yet little information is available about sleep disorders according to the type of epileptic seizures. Materials and methods. The sleep architecture of rats was evaluated in polysomnography recordings 36 hours after inducing partial and generalised epileptic seizures in them. The epileptic seizures were induced by applying 50-100 IU of sodium G penicillin in the amygdala of the temporal lobe. Results. Partial and generalised seizures triggered an increase in the latency of slow wave sleep (SWS) and rapid eye movement (REM) sleep. The number of episodes of the phases of wakefulness, SWS and REM sleep was reduced and the mean duration of the episodes of wakefulness and SWS increased, while that of REM sleep diminished. The total percentage of REM sleep diminished signifi cantly. During the first period of light the partial and generalised seizures triggered an increase in wakefulness and a reduction in the phases of SWS and REM sleep. In the period of darkness, the SWS increased and wakefulness decreased, while there were no changes in REM sleep. In the second period of light, the percentages of the phases of wakefulness and SWS returned to control values and the percentage of REM sleep continued to be reduced. Conclusions. Changes in the structuring of sleep depend on the type of epileptic seizure that presents. Generalised epileptic seizures caused greater deterioration in REM sleep (AU)

[Effect of partial and generalised epileptic seizures on sleep architecture in rats]. / Efecto de las crisis epilépticas parciales y generalizadas sobre la arquitectura del sueño en ratas.

INTRODUCTION: It is a well-known fact that epileptic seizures disrupt sleep, yet little information is available about sleep disorders according to the type of epileptic seizures. MATERIALS AND METHODS: The sleep architecture of rats was evaluated in polysomnography recordings 36 hours after inducing partial and generalised epileptic seizures in them. The epileptic seizures were induced by applying 50-100 IU of sodium G penicillin in the amygdala of the temporal lobe. RESULTS: Partial and generalised seizures triggered an increase in the latency of slow wave sleep (SWS) and rapid eye movement (REM) sleep. The number of episodes of the phases of wakefulness, SWS and REM sleep was reduced and the mean duration of the episodes of wakefulness and SWS increased, while that of REM sleep diminished. The total percentage of REM sleep diminished significantly. During the first period of light the partial and generalised seizures triggered an increase in wakefulness and a reduction in the phases of SWS and REM sleep. In the period of darkness, the SWS increased and wakefulness decreased, while there were no changes in REM sleep. In the second period of light, the percentages of the phases of wakefulness and SWS returned to control values and the percentage of REM sleep continued to be reduced. CONCLUSIONS: Changes in the structuring of sleep depend on the type of epileptic seizure that presents. Generalised epileptic seizures caused greater deterioration in REM sleep.

TITLE: Efecto de las crisis epilepticas parciales y generalizadas sobre la arquitectura del sueño en ratas.Introduccion. La alteracion del sueño producido por las crisis epilepticas se conoce; sin embargo, aun se tiene poca informacion de la alteracion en el sueño por el tipo de crisis epileptica. Materiales y metodos. Se evaluo la arquitectura del sueño de ratas en registros polisomnograficos de 36 horas tras inducirles crisis epilepticas parciales y generalizadas. Para la induccion de las crisis epilepticas se aplicaron in situ 50-100 UI de penicilina G sodica en la amigdala del lobulo temporal. Resultados. Las crisis parciales y generalizadas provocaron el aumento en la latencia del sueño de ondas lentas (SOL) y sueño de movimiento oculares rapidos (MOR). El numero de episodios de las fases de vigilia, SOL y sueño MOR disminuyo y la duracion media de los episodios de la vigilia y del SOL aumento, mientras que la del sueño MOR disminuyo. El porcentaje total del sueño MOR disminuyo significativamente. Durante el primer periodo de luz, las crisis parciales y generalizadas provocaron el incremento de la vigilia y la reduccion de las fases del SOL y sueño MOR. En el periodo de oscuridad, aumento el SOL, disminuyo la vigilia y no hubo cambios en el sueño MOR. En el segundo periodo de luz los porcentajes de las fases de vigilia y SOL regresaron a los valores control y el porcentaje del sueño MOR continuo disminuido. Conclusion. Los cambios en la organizacion del sueño dependen del tipo de crisis epileptica que se presenta. Las crisis epilepticas generalizadas provocaron mayor deterioro en el sueño MOR.

Differential contributions of microglial and neuronal IKKß to synaptic plasticity and associative learning in alert behaving mice.

Microglia are CNS resident immune cells and a rich source of neuroactive mediators, but their contribution to physiological brain processes such as synaptic plasticity, learning, and memory is not fully understood. In this study, we used mice with partial depletion of IκB kinase ß, the main activating kinase in the inducible NF-κB pathway, selectively in myeloid lineage cells (mIKKßKO) or excitatory neurons (nIKKßKO) to measure synaptic strength at hippocampal Schaffer collaterals during long-term potentiation (LTP) and instrumental conditioning in alert behaving individuals. Resting microglial cells in mIKKßKO mice showed less Iba1-immunoreactivity, and brain IL-1ß mRNA levels were selectively reduced compared with controls. Measurement of field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of the CA3-CA1 synapse in mIKKßKO mice showed higher facilitation in response to paired pulses and enhanced LTP following high frequency stimulation. In contrast, nIKKßKO mice showed normal basic synaptic transmission and LTP induction but impairments in late LTP. To understand the consequences of such impairments in synaptic plasticity for learning and memory, we measured CA1 fEPSPs in behaving mice during instrumental conditioning. IKKß was not necessary in either microglia or neurons for mice to learn lever-pressing (appetitive behavior) to obtain food (consummatory behavior) but was required in both for modification of their hippocampus-dependent appetitive, not consummatory behavior. Our results show that microglia, through IKKß and therefore NF-κB activity, regulate hippocampal synaptic plasticity and that both microglia and neurons, through IKKß, are necessary for animals to modify hippocampus-driven behavior during associative learning.

Involvement of the GABAergic septo-hippocampal pathway in brain stimulation reward.

The hippocampus is a structure related to several cognitive processes, but not very much is known about its putative involvement in positive reinforcement. In its turn, the septum has been related to instrumental brain stimulation reward (BSR) by its electrical stimulation with trains of pulses. Although the anatomical relationships of the septo-hippocampal pathway are well established, the functional relationship between these structures during rewarding behaviors remains poorly understood. To explore hippocampal mechanisms involved in BSR, CA3-evoked field excitatory and inhibitory postsynaptic potentials (fEPSPs, fIPSPs) were recorded in the CA1 area during BSR in alert behaving mice. The synaptic efficiency was determined from changes in fEPSP and fIPSP amplitudes across the learning of a BSR task. The successive BSR sessions evoked a progressive increase of the performance in inverse relationship with a decrease in the amplitude of fEPSPs, but not of fIPSPs. Additionally, we evaluated CA1 local field potentials (LFPs) during a preference task, comparing 8-, 20-, and 100-Hz trains of septal BSR. We corroborate a clear preference for BSR at 100 Hz (in comparison with BSR at 20 Hz or 8 Hz), in parallel with an increase in the spectral power of the low theta band, and a decrease in the gamma. These results were replicated by intrahippocampal injections of a GABAB antagonist. Thus, the GABAergic septo-hippocampal pathway seems to carry information involved in the encoding of reward properties, where GABAB receptors seem to play a key role. With regard to the dorsal hippocampus, fEPSPs evoked at the CA3-CA1 synapse seem to reflect the BSR learning process, while hippocampal rhythmic activities are more related to reward properties.

The GABAergic septohippocampal pathway is directly involved in internal processes related to operant reward learning.

We studied the role of γ-aminobutyric acid (GABA)ergic septohippocampal projections in medial septum (MS) self-stimulation of behaving mice. Self-stimulation was evoked in wild-type (WT) mice using instrumental conditioning procedures and in J20 mutant mice, a type of mouse with a significant deficit in GABAergic septohippocampal projections. J20 mice showed a significant modification in hippocampal activities, including a different response for input/output curves and the paired-pulse test, a larger long-term potentiation (LTP), and a delayed acquisition and lower performance in the MS self-stimulation task. LTP evoked at the CA3-CA1 synapse further decreased self-stimulation performance in J20, but not in WT, mice. MS self-stimulation evoked a decrease in the amplitude of field excitatory postsynaptic potentials (fEPSPs) at the CA3-CA1 synapse in WT, but not in J20, mice. This self-stimulation-dependent decrease in the amplitude of fEPSPs was also observed in the presence of another positive reinforcer (food collected during an operant task) and was canceled by the local administration of an antibody-inhibiting glutamate decarboxylase 65 (GAD65). LTP evoked in the GAD65Ab-treated group was also larger than in controls. The hippocampus has a different susceptibility to septal GABAergic inputs depending on ongoing cognitive processes, and the GABAergic septohippocampal pathway is involved in consummatory processes related to operant rewards.

Accelerated aging of the GABAergic septohippocampal pathway and decreased hippocampal rhythms in a mouse model of Alzheimer's disease.

Patients with Alzheimer's disease (AD) display altered functioning of cortical networks, including altered patterns of synchronous activity and a serious deficit in cholinergic septohippocampal (SH) innervation. However, the mechanisms underlying these alterations and the implication of the GABAergic SH component in AD are largely unknown. In addition, the GABAergic septohippocampal pathway (SHP) is believed to regulate synchronous hippocampal activity by controlling the activity of interneurons. Here we show, using well-characterized pathway tracing experiments, that innervation of the GABAergic SHP decreases during normal aging. Furthermore, in an AD mouse model (hAPP(Sw,Ind); J20 mice), the GABAergic SHP shows a dramatic and early onset of this decrease in 8-mo-old mice. This decline is not caused by neuronal loss, but by the reduced number and complexity of GABAergic SH axon terminals. Finally, we demonstrate that hippocampal θ and γ rhythm power spectra are markedly diminished in 8-mo-old behaving mice expressing mutated hAPP. In addition to the well-known loss of cholinergic input to the hippocampus in AD, these data suggest that the altered patterns of synchronous activity seen in patients with AD could be caused by the loss of GABAergic SH axons, which modulate hippocampal network activities.