Network Asynchrony Underlying Increased Broadband Gamma Power.

Synchronous activity of cortical inhibitory interneurons expressing parvalbumin (PV) underlies expression of cortical γ rhythms. Paradoxically, deficient PV inhibition is associated with increased broadband γ power in the local field potential. Increased baseline broadband γ is also a prominent characteristic in schizophrenia and a hallmark of network alterations induced by NMDAR antagonists, such as ketamine. Whether enhanced broadband γ is a true rhythm, and if so, whether rhythmic PV inhibition is involved or not, is debated. Asynchronous and increased firing activities are thought to contribute to broadband power increases spanning the γ band. Using male and female mice lacking NMDAR activity specifically in PV neurons to model deficient PV inhibition, we here show that neuronal activity with decreased synchronicity is associated with increased prefrontal broadband γ power. Specifically, reduced spike time precision and spectral leakage of spiking activity because of higher firing rates (spike "contamination") affect the broadband γ band. Desynchronization was evident at multiple time scales, with reduced spike entrainment to the local field potential, reduced cross-frequency coupling, and fragmentation of brain states. Local application of S(+)-ketamine in (control) mice with intact NMDAR activity in PV neurons triggered network desynchronization and enhanced broadband γ power. However, our investigations suggest that disparate mechanisms underlie increased broadband γ power caused by genetic alteration of PV interneurons and ketamine-induced power increases in broadband γ. Our study confirms that enhanced broadband γ power can arise from asynchronous activities and demonstrates that long-term deficiency of PV inhibition can be a contributor.SIGNIFICANCE STATEMENT Brain oscillations are fundamental to the coordination of neuronal activity across neurons and structures. γ oscillations (30-80 Hz) have received particular attention through their association with perceptual and cognitive processes. Synchronous activity of inhibitory parvalbumin (PV) interneurons generates cortical γ oscillation, but, paradoxically, PV neuron deficiency is associated with increases in γ oscillations. We here reconcile this conundrum and show how deficient PV inhibition can lead to increased and asynchronous excitatory firing, contaminating the local field potential and manifesting as increased γ power. Thus, increased γ power does not always reflect a genuine rhythm. Further, we show that ketamine-induced γ increases are caused by separate network mechanisms.

Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics.

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of γ oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.SIGNIFICANCE STATEMENT Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling promotes the maturation of inhibitory parvalbumin (PV) interneurons, neurons central to local cortical dynamics, γ rhythms, and cognition. Here, we used a novel viral approach for reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) to establish the role of BDNF/trkB signaling in adult prefrontal network activities. Reduced BDNF/trkB signaling caused pronounced morphologic alterations, reduced PV inhibition, and deficient prefrontal network dynamics. The altered network activity appeared to manifest across stimuli and brain states and was associated with aberrant local field potential (LFP) activities and increased aggression. The results demonstrate that adult BDNF/trkB signaling is essential to PV inhibition and prefrontal circuit function and directly links BDNF/trkB signaling to network integrity in the adult brain.

Clusters of cerebellar Purkinje cells control their afferent climbing fiber discharge.

Climbing fibers, the projections from the inferior olive to the cerebellar cortex, carry sensorimotor error and clock signals that trigger motor learning by controlling cerebellar Purkinje cell synaptic plasticity and discharge. Purkinje cells target the deep cerebellar nuclei, which are the output of the cerebellum and include an inhibitory GABAergic projection to the inferior olive. This pathway identifies a potential closed loop in the olivo-cortico-nuclear network. Therefore, sets of Purkinje cells may phasically control their own climbing fiber afferents. Here, using in vitro and in vivo recordings, we describe a genetically modified mouse model that allows the specific optogenetic control of Purkinje cell discharge. Tetrode recordings in the cerebellar nuclei demonstrate that focal stimulations of Purkinje cells strongly inhibit spatially restricted sets of cerebellar nuclear neurons. Strikingly, such stimulations trigger delayed climbing-fiber input signals in the stimulated Purkinje cells. Therefore, our results demonstrate that Purkinje cells phasically control the discharge of their own olivary afferents and thus might participate in the regulation of cerebellar motor learning.

Functional role of the cerebellum in gamma-band synchronization of the sensory and motor cortices.

The cerebellum is an essential structure for the control of movement. It sends abundant ascending projections to the cerebral cortex via the thalamus, but its contribution to cortical activity remains largely unknown. Here we studied its influence on cortical neuronal activity in freely moving rats. We demonstrate an excitatory action of the cerebellum on the motor thalamus and the motor cortex. We also show that cerebellar inactivation disrupts the gamma-band coherence of local field potential between the sensory and motor cortices during whisking. In contrast, phase locking of neuronal activities to local gamma oscillations was preserved in the sensory and motor cortices by cerebellar inactivation. These results indicate that the cerebellum contributes to coordinated sensorimotor cortical activities during motor activation and thus participates in the multiregional cortical processing of information.

Cerebellum involvement in cortical sensorimotor circuits for the control of voluntary movements.

Sensorimotor integration is crucial to perception and motor control. How and where this process takes place in the brain is still largely unknown. Here we analyze the cerebellar contribution to sensorimotor integration in the whisker system of mice. We identify an area in the cerebellum where cortical sensory and motor inputs converge at the cellular level. Optogenetic stimulation of this area affects thalamic and motor cortex activity, alters parameters of ongoing movements and thereby modifies qualitatively and quantitatively touch events against surrounding objects. These results shed light on the cerebellum as an active component of sensorimotor circuits and show the importance of sensorimotor cortico-cerebellar loops in the fine control of voluntary movements.

The first mecp2-null zebrafish model shows altered motor behaviors.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder and one of the most common causes of mental retardation in affected girls. Other symptoms include a rapid regression of motor and cognitive skills after an apparently early normal development. Sporadic mutations in the transcription factor MECP2 has been shown to be present in more than 90% of the patients and several models of MeCP2-deficient mice have been created to understand the role of this gene. These models have pointed toward alterations in the maintenance of the central nervous system rather than its development, in line with the late onset of the disease in humans. However, the exact functions of MeCP2 remain difficult to delineate and the animal models have yielded contradictory results. Here, we present the first mecp2-null allele mutation zebrafish model. Surprisingly and in contrast to MeCP2-null mouse models, mecp2-null zebrafish are viable and fertile. They present nonetheless clear behavioral alterations during their early development, including spontaneous and sensory-evoked motor anomalies, as well as defective thigmotaxis.

Behavioral evidence for differences in social and non-social category learning.

When meeting someone for the very first time one spontaneously categorizes the seen person on the basis of his/her appearance. Categorization is based on the association between some physical features and category labels that can be social (character trait…) or non-social (tall, thin). Surprisingly little is known about how such associations are formed, particularly in the social domain. Here, we aimed at testing whether social and non-social category learning may be dissociated. We presented subjects with a large number of faces that had to be rated according to social or non-social labels, and induced an association between a facial feature (inter-eye distance) and the category labels using two different procedures. In a first experiment, we used a feedback procedure to reinforce the association; behavioral measures revealed an association between the physical feature manipulated and abstract non-social categories, while no evidence for an association with social labels could be found. In a second experiment, we used passive exposure to the association between physical features and labels; we obtained behavioral evidence for learning of both social and non-social categories. These results support the view of the specificity of social category learning; they suggest that social categories are best acquired through unsupervised procedures that can be considered as a simplified proxy for group transmission.

Time determines the neural circuit underlying associative fear learning.

Ultimately associative learning is a function of the temporal features and relationships between experienced stimuli. Nevertheless how time affects the neural circuit underlying this form of learning remains largely unknown. To address this issue, we used single-trial auditory trace fear conditioning and varied the length of the interval between tone and foot-shock. Through temporary inactivation of the amygdala, medial prefrontal-cortex (mPFC), and dorsal-hippocampus in rats, we tested the hypothesis that different temporal intervals between the tone and the shock influence the neuronal structures necessary for learning. With this study we provide the first experimental evidence showing that temporarily inactivating the amygdala before training impairs auditory fear learning when there is a temporal gap between the tone and the shock. Moreover, imposing a short interval (5 s) between the two stimuli also relies on the mPFC, while learning the association across a longer interval (40 s) becomes additionally dependent on a third structure, the dorsal-hippocampus. Thus, our results suggest that increasing the interval length between tone and shock leads to the involvement of an increasing number of brain areas in order for the association between the two stimuli to be acquired normally. These findings demonstrate that the temporal relationship between events is a key factor in determining the neuronal mechanisms underlying associative fear learning.