68 research outputs found
Astrocyte-Derived Adenosine and A1 Receptor Activity Contribute to Sleep Loss-Induced Deficits in Hippocampal Synaptic Plasticity and Memory in Mice
No full textSleep deprivation (SD) can have a negative impact on cognitive function, but the mechanism(s) by which SD modulates memory remains unclear. We have previously shown that astrocyte-derived adenosine is a candidate molecule involved in the cognitive deficits following a brief period of SD (Halassa et al., 2009). In this study, we examined whether genetic disruption of soluble N-ethylmaleimide-sensitive factor attached protein (SNARE)-dependent exocytosis in astrocytes (dnSNARE mice) or pharmacological blockade of A1 receptor signaling using an adenosine A1 receptor (A1R) antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT), could prevent the negative effects of 6 h of SD on hippocampal late-phase long-term potentiation (L-LTP) and hippocampus-dependent spatial object recognition memory. We found that SD impaired L-LTP in wild-type mice but not in dnSNARE mice. Similarly, this deficit in L-LTP resulting from SD was prevented by a chronic infusion of CPT. Consistent with these results, we found that hippocampus-dependent memory deficits produced by SD were rescued in dnSNARE mice and CPT-treated mice. These data provide the first evidence that astrocytic ATP and adenosine A1R activity contribute to the effects of SD on hippocampal synaptic plasticity and hippocampus-dependent memory, and suggest a new therapeutic target to reverse the hippocampus-related cognitive deficits induced by sleep loss.United States. National Institutes of Health (P50 Grant AG017628)United States. National Institutes of Health (Training Grant HL07953)United States. National Institutes of Health (Grant R01 NS037585)United States. National Institutes of Health (Grant R01 NS043142
Astrocyte regulation of sleep circuits: experimental and modeling perspectives
No full textIntegrated within neural circuits, astrocytes have recently been shown to modulate brain rhythms thought to mediate sleep function. Experimental evidence suggests that local impact of astrocytes on single synapses translates into global modulation of neuronal networks and behavior. We discuss these findings in the context of current conceptual models of sleep generation and function, each of which have historically focused on neural mechanisms. We highlight the implications and the challenges introduced by these results from a conceptual and computational perspective. We further provide modeling directions on how these data might extend our knowledge of astrocytic properties and sleep function. Given our evolving understanding of how local cellular activities during sleep lead to functional outcomes for the brain, further mechanistic and theoretical understanding of astrocytic contribution to these dynamics will undoubtedly be of great basic and translational benefit.National Institute of Neurological Disorders and Stroke (U.S.
Integrated Brain Circuits: Neuron-Astrocyte Interaction in Sleep-Related Rhythmogenesis
No full textAlthough astrocytes are increasingly recognized as important modulators of neuronal excitability and information transfer at the synapse, whether these cells regulate neuronal network activity has only recently started to be investigated. In this article, we highlight the role of astrocytes in the modulation of circuit function with particular focus on sleep-related rhythmogenesis. We discuss recent data showing that these glial cells regulate slow oscillations, a specific thalamocortical activity that characterizes non-REM sleep, and sleep-associated behaviors. Based on these findings, we predict that our understanding of the genesis and tuning of thalamocortical rhythms will necessarily go through an integrated view of brain circuits in which non-neuronal cells can play important neuromodulatory roles.Italy. Ministero dell'istruzione, dell'universita e della ricercaTelethon-Italy (GGP09134
Thalamocortical Circuit Motifs: A General Framework
No full textThe role of the thalamus in cortical sensory transmission is well known, but its broader role in cognition is less appreciated. Recent studies have shown thalamic engagement in dynamic regulation of cortical activity in attention, executive control, and perceptual decision-making, but the circuit mechanisms underlying such functionality are unknown. Because the thalamus is composed of excitatory neurons that are devoid of local recurrent excitatory connectivity, delineating long-range, input-output connectivity patterns of single thalamic neurons is critical for building functional models. We discuss this need in relation to existing organizational schemes such as core versus matrix and first-order versus higher-order relay nuclei. We propose that a new classification is needed based on thalamocortical motifs, where structure naturally informs function. Overall, our synthesis puts understanding thalamic organization at the forefront of existing research in systems and computational neuroscience, with both basic and translational applications. Halassa and Sherman highlight the role of the thalamus in cortical function and the lack of knowledge surrounding thalamocortical connectivity at single-cell resolution. They propose thalamocortical motifs as units of organization with potential to inform cognitively relevant functional models
Integrated Brain Circuits: Neuron-Astrocyte Interaction in Sleep-Related Rhythmogenesis
No full textAlthough astrocytes are increasingly recognized as important modulators of neuronal excitability and information transfer at the synapse, whether these cells regulate neuronal network activity has only recently started to be investigated. In this article, we highlight the role of astrocytes in the modulation of circuit function with particular focus on sleep-related rhythmogenesis. We discuss recent data showing that these glial cells regulate slow oscillations, a specific thalamocortical activity that characterizes non-REM sleep, and sleep-associated behaviors. Based on these findings, we predict that our understanding of the genesis and tuning of thalamocortical rhythms will necessarily go through an integrated view of brain circuits in which non-neuronal cells can play important neuromodulatory roles
Sensation during Active Behaviors
No full textA substantial portion of our sensory experience happens during active behaviors such as walking around or paying attention. How do sensory systems work during such behaviors? Neural processing in sensory systems can be shaped by behavior in multiple ways ranging from a modulation of responsiveness or sharpening of tuning to a dynamic change of response properties or functional connectivity. Here, we review recent findings on the modulation of sensory processing during active behaviors in different systems: insect vision, rodent thalamus, and rodent sensory cortices. We discuss the circuit-level mechanisms that might lead to these modulations and their potential role in sensory function. Finally, we highlight the open questions and future perspectives of this exciting new field
State-Dependent Architecture of Thalamic Reticular Subnetworks
No full textBehavioral state is known to influence interactions between thalamus and cortex, which are important for sensation, action, and cognition. The thalamic reticular nucleus (TRN) is hypothesized to regulate thalamo-cortical interactions, but the underlying functional architecture of this process and its state dependence are unknown. By combining the first TRN ensemble recording with psychophysics and connectivity-based optogenetic tagging, we found reticular circuits to be composed of distinct subnetworks. While activity of limbic-projecting TRN neurons positively correlates with arousal, sensory-projecting neurons participate in spindles and show elevated synchrony by slow waves during sleep. Sensory-projecting neurons are suppressed by attentional states, demonstrating that their gating of thalamo-cortical interactions is matched to behavioral state. Bidirectional manipulation of attentional performance was achieved through subnetwork-specific optogenetic stimulation. Together, our findings provide evidence for differential inhibition of thalamic nuclei across brain states, where the TRN separately controls external sensory and internal limbic processing facilitating normal cognitive function.National Institute of Neurological Disorders and Stroke (U.S.) (NIH Pathway to Independence Career Award K99 NS 078115)Brain & Behavior Research Foundation (Young Investigator Award)National Institutes of Health (U.S.) ( Transformative R01 Award TR01-GM10498)National Institutes of Health (U.S.) (Grant R01-MH061976
Genetic variability of memory performance is explained by differences in the brain’s thalamus
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Neuromodulatory roles for astrocytes: Synapses, circuits & behavior
No full textIn addition to being structurally associated with synapses, astrocytes are now known to be functionally involved in the modulation of synaptic transmission. Astrocytes express a number of G-protein coupled receptors (GPCRs) which allow them to respond to nearby synaptic activity by an IP 3-dependent rise in intracellular Ca2+. Fifteen years ago, the Haydon lab discovered that astrocytes are able to release chemical transmitters that influence nearby neurons in a process termed gliotransmission, demonstrating that astrocytes not only “listen” to synapses, but can also “talk” back. In my thesis, I first describe the detailed three dimensional relationships between astrocytes and neurons in the mammalian neocortex. I show that cortical astrocytes occupy non-overlapping territories and that a single astrocyte contacts, on average, four neuronal cell bodies and hundreds of dendrites. Second, I generate a transgenic animal in which a venus-tagged IP 3 5-phosphatase (VIPP) fusion protein is selectively and conditionally expressed in astrocytes to attenuate IP3-dependent Ca2+ signaling. In hippocampal suces derived from the VIPP mice, agonist induced Ca2+ signaling in astrocytes and theta-burst induced LTP are significantly attenuated. Third, by using a transgenic animal in which SNARE-dependent gliotransmission is attenuated by the overexpression of a dominant negative SNARE domain (dnSNARE) specifically and conditionally in astrocytes, I show that sleep homeostasis and memory impairment following sleep loss are under the control of astrocytic adenosine. I corroborate these findings by an independent pharmacological approach in vivo. This study is the first to show a direct behavioral consequence for gliotransmission in mammals. Combined these studies offer an insight into the structural and functional relationship between astrocytes and neurons and to the role of gliotransmission in controlling synapses, circuits and behavior
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