Prefrontal Parvalbumin Neurons in Control of Attention

SummaryWhile signatures of attention have been extensively studied in sensory systems, the neural sources and computations responsible for top-down control of attention are largely unknown. Using chronic recordings in mice, we found that fast-spiking parvalbumin (FS-PV) interneurons in medial prefrontal cortex (mPFC) uniformly show increased and sustained firing during goal-driven attentional processing, correlating to the level of attention. Elevated activity of FS-PV neurons on the timescale of seconds predicted successful execution of behavior. Successful allocation of attention was characterized by strong synchronization of FS-PV neurons, increased gamma oscillations, and phase locking of pyramidal firing. Phase-locked pyramidal neurons showed gamma-phase-dependent rate modulation during successful attentional processing. Optogenetic silencing of FS-PV neurons deteriorated attentional processing, while optogenetic synchronization of FS-PV neurons at gamma frequencies had pro-cognitive effects and improved goal-directed behavior. FS-PV neurons thus act as a functional unit coordinating the activity in the local mPFC circuit during goal-driven attentional processing

A Whole-Brain Atlas of Inputs to Serotonergic Neurons of the Dorsal and Median Raphe Nuclei

SummaryThe serotonin system is proposed to regulate physiology and behavior and to underlie mood disorders; nevertheless, the circuitry controlling serotonergic neurons remains uncharacterized. We therefore generated a comprehensive whole-brain atlas defining the monosynaptic inputs onto forebrain-projecting serotonergic neurons of dorsal versus median raphe based on a genetically restricted transsynaptic retrograde tracing strategy. We identified discrete inputs onto serotonergic neurons from forebrain and brainstem neurons, with specific inputs from hypothalamus, cortex, basal ganglia, and midbrain, displaying a greater than anticipated complexity and diversity in cell-type-specific connectivity. We identified and functionally confirmed monosynaptic glutamatergic inputs from prefrontal cortex and lateral habenula onto serotonergic neurons as well as a direct GABAergic input from striatal projection neurons. In summary, our findings emphasize the role of hyperdirect inputs to serotonergic neurons. Cell-type-specific classification of connectivity patterns will allow for further functional analysis of the diverse but specific inputs that control serotonergic neurons during behavior

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 frag- mentation of brain states. Local application of S(1)-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 c. Our study confirms that enhanced broadband γ power can arise from asynchronous activ- ities and demonstrates that long-term deficiency of PV inhibition can be a contributor.ERCSTINT Program Joint Brazilian-Swedish Research Collaboration GrantCAPES-STINT Program GrantKnut and Alice Wallenberg FoundationSwedish Research CouncilKarolinska InstitutetAccepte

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 c 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.ERCSwedish Research CouncilCAPES-STINT Program GrantKarolinska InstitutetKnut and Alice Wallenberg FoundationSTINT Program Joint Brazilian-Swedish Research Collaboration GrantPublishe

Driving fast-spiking cells induces gamma rhythm and controls sensory responses,”

Cortical gamma oscillations (20280 Hz) predict increases in focused attention, and failure in gamma regulation is a hallmark of neurological and psychiatric disease. Current theory predicts that gamma oscillations are generated by synchronous activity of fast-spiking inhibitory interneurons, with the resulting rhythmic inhibition producing neural ensemble synchrony by generating a narrow window for effective excitation. We causally tested these hypotheses in barrel cortex in vivo by targeting optogenetic manipulation selectively to fast-spiking interneurons. Here we show that light-driven activation of fast-spiking interneurons at varied frequencies (82200 Hz) selectively amplifies gamma oscillations. In contrast, pyramidal neuron activation amplifies only lower frequency oscillations, a cell-type-specific double dissociation. We found that the timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses. Our data directly support the fast-spiking-gamma hypothesis and provide the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation. Brain states characterized by rhythmic electrophysiological activity have been studied intensively for more than 80 years Cell-type-specific expression of channelrhodopsin-2 To test directly the hypothesis that FS interneuron activity in an in vivo cortical circuit is sufficient to induce gamma oscillations, we used the light-sensitive bacteriorhodopsin Chlamydomonas reinhardtii channelrhodopsin-2 (ChR2), a cation channel activated by ,470 nm blue ligh

Spinal Cord Injury Reveals Multilineage Differentiation of Ependymal Cells

Spinal cord injury often results in permanent functional impairment. Neural stem cells present in the adult spinal cord can be expanded in vitro and improve recovery when transplanted to the injured spinal cord, demonstrating the presence of cells that can promote regeneration but that normally fail to do so efficiently. Using genetic fate mapping, we show that close to all in vitro neural stem cell potential in the adult spinal cord resides within the population of ependymal cells lining the central canal. These cells are recruited by spinal cord injury and produce not only scar-forming glial cells, but also, to a lesser degree, oligodendrocytes. Modulating the fate of ependymal progeny after spinal cord injury may offer an alternative to cell transplantation for cell replacement therapies in spinal cord injury

Adult neurogenesis : From stem cell to functional neuron

The adult mammalian central nervous system harbors a population of neural stem cells with the ability to generate neurons, astrocytes and oligodendrocytes. These pluripotent cells can be enriched in vitro, and by directing their differentiation it would be possible to generate populations of specific neural cell types to use for transplantation. Alternatively, gene therapies stimulating stem cells directly in the brain to produce more neurons of a desired type could be an attractive treatment. It has proven difficult to express genes in stem cells. We have therefore established and evaluated different gene delivery methods, both viral and nonviral, for introduction of genes into adult neural stem cells in vitro and in vivo. Using these different techniques, we show that it is possible to target gene expression to stem cells in the adult brain, and also that it is feasible to direct the differentiation of the stem cells to neurons in vitro. In the adult mammalian brain stem cells give rise to new neurons in the olfactory bulb and the hippocampus. A question has been whether neurons born in the adult integrate into the existing neuronal network of the brain. Using a transsynaptically transported virus, we have shown that adult-born neurons in both the olfactory bulb and the hippocampus do integrate into existing circuit. Moreover, markers for neuronal activity show that a high degree of the neurons born in the adult olfactory bulb participate in odor processing, showing that adult-born neurons not only integrate, they also function as they respond to relevant environmental stimuli. The finding that ongoing neuronal cell death in the substantia nigra does not alter the total number of neurons in the same area indicates that new neurons are continuously added and compensate for the cell loss. We have therefore investigated the neurogenic potential in the substantia nigra of the midbrain, the region where dopamine-producing neurons lost in Parkinson's disease reside. Two different mitotic markers were found in dopaminergic neurons of the substantia nigra, and we identified ependymal cells lining the ventricles of the midbrain as the most likely origin for the newborn neurons. The adult-born dopaminergic neurons were found to project to their appropriate target and also to integrate into the existing synaptic network. Additionally, we could show that the rate of neurogenesis is increased after a selective lesion of dopaminergic neurons. This indicates that the rate of adult neurogenesis can be altered, a finding with implications for cellular therapies of Parkinson's disease. The regulation of neurogenesis from stem cells in the adult brain is largely unknown. Notch receptor signaling has been suggested to be involved. We found several Notch receptors and ligands, as well as downstream genes, to be expressed in the stem cell niche in the adult neurogenic lateral ventricle wall. Genetic manipulations in transgenic mice have shown that inhibition of Notch signaling in ependymal cells leads to differentiation of ependymal cells into neurons. These neurons migrate and mature similarly to neurons normally born in the lateral ventricle wall. This demonstrates that Notch signaling keeps ependymal cells in a quiescent state and that ablation of this signaling pathway induces neurogenesis by ependymal cells in vivo. This further supports the finding of ependymal cells acting as neural stem cells in the adult brain

Mice lacking NMDA receptors in parvalbumin neurons display normal depression-related behavior and response to antidepressant action of NMDAR antagonists.

The underlying circuit imbalance in major depression remains unknown and current therapies remain inadequate for a large group of patients. Discovery of the rapid antidepressant effects of ketamine--an NMDA receptor (NMDAR) antagonist--has linked the glutamatergic system to depression. Interestingly, dysfunction in the inhibitory GABAergic system has also been proposed to underlie depression and deficits linked to GABAergic neurons have been found with human imaging and in post-mortem material from depressed patients. Parvalbumin-expressing (PV) GABAergic interneurons regulate local circuit function through perisomatic inhibition and their activity is NMDAR-dependent, providing a possible link between NMDAR and the inhibitory system in the antidepressant effect of ketamine. We have therefore investigated the role of the NMDAR-dependent activity of PV interneurons for the development of depression-like behavior as well as for the response to rapid antidepressant effects of NMDAR antagonists. We used mutant mice lacking NMDA neurotransmission specifically in PV neurons (PV-Cre+/NR1f/f) and analyzed depression-like behavior and anhedonia. To study the acute and sustained effects of a single NMDAR antagonist administration, we established a behavioral paradigm of repeated exposure to forced swimming test (FST). We did not observe altered behavioral responses in the repeated FST or in a sucrose preference test in mutant mice. In addition, the behavioral response to administration of NMDAR antagonists was not significantly altered in mutant PV-Cre+/NR1f/f mice. Our results show that NMDA-dependent neurotransmission in PV neurons is not necessary to regulate depression-like behaviors, and in addition that NMDARs on PV neurons are not a direct target for the NMDAR-induced antidepressant effects of ketamine and MK801

Mice display stable behavior in a repeated FST paradigm.

<p>(A) Outline of the repeated FST protocol performed over several days. C57BL/6N mice (n = 12) were injected at time 0 with saline (arrow) and every mouse was subjected to FST 30 min, 24 h, 48 h, 72 h and 96 h later. After 4 days of rest in their home cages mice were retested in the FST once again (i.e. 240 h after saline injection). (B) Results (sec/4 min) are presented as mean values ±SEM. Immobility time is stable after repeated FST: 161±15 (30 min); 173±17 (24 h); 199±12 (48 h); 208±9 (72 h); 186±9 (96 h) and 183±9 (240 h) (p>0.05, one way ANOVA).</p

Cell-type-specific representation of spatial context in the rat prefrontal cortex

Summary: The ability to represent one’s own position in relation to cues, goals, or threats is crucial to successful goal-directed behavior. Using optotagging in knock-in rats expressing Cre recombinase in parvalbumin (PV) neurons (PV-Cre rats), we demonstrate cell-type-specific encoding of spatial and movement variables in the medial prefrontal cortex (mPFC) during goal-directed reward seeking. Single neurons encoded the conjunction of the animal’s spatial position and the run direction, referred to as the spatial context. The spatial context was most prominently represented by the inhibitory PV interneurons. Movement toward the reward was signified by increased local field potential (LFP) oscillations in the gamma band but this LFP signature was not related to the spatial information in the neuronal firing. The results highlight how spatial information is incorporated into cognitive operations in the mPFC. The presented PV-Cre line opens the door for expanded research approaches in rats