Thalamic Inhibition: Diverse Sources, Diverse Scales.

The thalamus is the major source of cortical inputs shaping sensation, action, and cognition. Thalamic circuits are targeted by two major inhibitory systems: the thalamic reticular nucleus (TRN) and extrathalamic inhibitory (ETI) inputs. A unifying framework of how these systems operate is currently lacking. Here, we propose that TRN circuits are specialized to exert thalamic control at different spatiotemporal scales. Local inhibition of thalamic spike rates prevails during attentional selection, whereas global inhibition more likely prevails during sleep. In contrast, the ETI (arising from basal ganglia, zona incerta (ZI), anterior pretectum, and pontine reticular formation) provides temporally precise and focal inhibition, impacting spike timing. Together, these inhibitory systems allow graded control of thalamic output, enabling thalamocortical operations to dynamically match ongoing behavioral demands

The thalamus in psychosis spectrum disorder

Psychosis spectrum disorder (PSD) affects 1% of the world population and results in a lifetime of chronic disability, causing devastating personal and economic consequences. Developing new treatments for PSD remains a challenge, particularly those that target its core cognitive deficits. A key barrier to progress is the tenuous link between the basic neurobiological understanding of PSD and its clinical phenomenology. In this perspective, we focus on a key opportunity that combines innovations in non-invasive human neuroimaging with basic insights into thalamic regulation of functional cortical connectivity. The thalamus is an evolutionary conserved region that forms forebrain-wide functional loops critical for the transmission of external inputs as well as the construction and update of internal models. We discuss our perspective across four lines of evidence: First, we articulate how PSD symptomatology may arise from a faulty network organization at the macroscopic circuit level with the thalamus playing a central coordinating role. Second, we discuss how recent animal work has mechanistically clarified the properties of thalamic circuits relevant to regulating cortical dynamics and cognitive function more generally. Third, we present human neuroimaging evidence in support of thalamic alterations in PSD, and propose that a similar “thalamocortical dysconnectivity” seen in pharmacological imaging (under ketamine, LSD and THC) in healthy individuals may link this circuit phenotype to the common set of symptoms in idiopathic and drug-induced psychosis. Lastly, we synthesize animal and human work, and lay out a translational path for biomarker and therapeutic development

State-Dependent Architecture of Thalamic Reticular Subnetworks

Behavioral 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

Design and Fabrication of Ultralight Weight, Adjustable Multi-electrode Probes for Electrophysiological Recordings in Mice

The number of physiological investigations in the mouse, mus musculus, has experienced a recent surge, paralleling the growth in methods of genetic targeting for microcircuit dissection and disease modeling. The introduction of optogenetics, for example, has allowed for bidirectional manipulation of genetically-identified neurons, at an unprecedented temporal resolution. To capitalize on these tools and gain insight into dynamic interactions among brain microcircuits, it is essential that one has the ability to record from ensembles of neurons deep within the brain of this small rodent, in both head-fixed and freely behaving preparations. To record from deep structures and distinct cell layers requires a preparation that allows precise advancement of electrodes towards desired brain regions. To record neural ensembles, it is necessary that each electrode be independently movable, allowing the experimenter to resolve individual cells while leaving neighboring electrodes undisturbed. To do both in a freely behaving mouse requires an electrode drive that is lightweight, resilient, and highly customizable for targeting specific brain structures. A technique for designing and fabricating miniature, ultralight weight, microdrive electrode arrays that are individually customizable and easily assembled from commercially available parts is presented. These devices are easily scalable and can be customized to the structure being targeted; it has been used successfully to record from thalamic and cortical regions in a freely behaving animal during natural behavior.Simons FoundationNational Institute of Neurological Disorders and Stroke (U.S.) (NIH Pathway to Independence Career Award)National Institutes of Health (U.S.

Modulation of prefrontal couplings by prior belief-related responses in ventromedial prefrontal cortex

Humans and other animals can maintain constant payoffs in an uncertain environment by steadily re-evaluating and flexibly adjusting current strategy, which largely depends on the interactions between the prefrontal cortex (PFC) and mediodorsal thalamus (MD). While the ventromedial PFC (vmPFC) represents the level of uncertainty (i.e., prior belief about external states), it remains unclear how the brain recruits the PFC-MD network to re-evaluate decision strategy based on the uncertainty. Here, we leverage non-linear dynamic causal modeling on fMRI data to test how prior belief-dependent activity in vmPFC gates the information flow in the PFC-MD network when individuals switch their decision strategy. We show that the prior belief-related responses in vmPFC had a modulatory influence on the connections from dorsolateral PFC (dlPFC) to both, lateral orbitofrontal (lOFC) and MD. Bayesian parameter averaging revealed that only the connection from the dlPFC to lOFC surpassed the significant threshold, which indicates that the weaker the prior belief, the less was the inhibitory influence of the vmPFC on the strength of effective connections from dlPFC to lOFC. These findings suggest that the vmPFC acts as a gatekeeper for the recruitment of processing resources to re-evaluate the decision strategy in situations of high uncertainty

Oxytocin Signaling in Mouse Taste Buds

The neuropeptide, oxytocin (OXT), acts on brain circuits to inhibit food intake. Mutant mice lacking OXT (OXT knockout) overconsume salty and sweet (i.e. sucrose, saccharin) solutions. We asked if OXT might also act on taste buds via its receptor, OXTR.Using RT-PCR, we detected the expression of OXTR in taste buds throughout the oral cavity, but not in adjacent non-taste lingual epithelium. By immunostaining tissues from OXTR-YFP knock-in mice, we found that OXTR is expressed in a subset of Glial-like (Type I) taste cells, and also in cells on the periphery of taste buds. Single-cell RT-PCR confirmed this cell-type assignment. Using Ca2+ imaging, we observed that physiologically appropriate concentrations of OXT evoked [Ca2+]i mobilization in a subset of taste cells (EC50 approximately 33 nM). OXT-evoked responses were significantly inhibited by the OXTR antagonist, L-371,257. Isolated OXT-responsive taste cells were neither Receptor (Type II) nor Presynaptic (Type III) cells, consistent with our immunofluorescence observations. We also investigated the source of OXT peptide that may act on taste cells. Both RT-PCR and immunostaining suggest that the OXT peptide is not produced in taste buds or in their associated nerves. Finally, we also examined the morphology of taste buds from mice that lack OXTR. Taste buds and their constituent cell types appeared very similar in mice with two, one or no copies of the OXTR gene.We conclude that OXT elicits Ca2+ signals via OXTR in murine taste buds. OXT-responsive cells are most likely a subset of Glial-like (Type I) taste cells. OXT itself is not produced locally in taste tissue and is likely delivered through the circulation. Loss of OXTR does not grossly alter the morphology of any of the cell types contained in taste buds. Instead, we speculate that OXT-responsive Glial-like (Type I) taste bud cells modulate taste signaling and afferent sensory output. Such modulation would complement central pathways of appetite regulation that employ circulating homeostatic and satiety signals

Astrocytes: biology and pathology

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions

Neuromodulatory roles for astrocytes: Synapses, circuits & behavior

In 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

Neuromodulatory roles for astrocytes: Synapses, circuits & behavior

In 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

Neuromodulatory roles for astrocytes: Synapses, circuits & behavior

In 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