Simple Summary In mammals, circadian rhythms in nearly all behaviors and physiological processes are controlled by the suprachiasmatic nucleus, a collection of neurons in the hypothalamus that synchronize the brain and body to local time. However, the circuits linking the suprachiasmatic nucleus to both the external world and to downstream targets are poorly understood. This review describes the inputs to and outputs from the suprachiasmatic nucleus. A better understanding of the circadian “connectome” is essential to determine how the disruption of these circuits can negatively impact human health. Abstract Circadian rhythms in mammals are coordinated by the central circadian pacemaker, the suprachiasmatic nucleus (SCN). Light and other environmental inputs change the timing of the SCN neural network oscillator, which, in turn, sends output signals that entrain daily behavioral and physiological rhythms. While much is known about the molecular, neuronal, and network properties of the SCN itself, the circuits linking the outside world to the SCN and the SCN to rhythmic outputs are understudied. In this article, we review our current understanding of the synaptic and non-synaptic inputs onto and outputs from the SCN. We propose that a more complete description of SCN connectivity is needed to better explain how rhythms in nearly all behaviors and physiological processes are generated and to determine how, mechanistically, these rhythms are disrupted by disease or lifestyle.

/pdf/inputs-and-outputs-of-the-mammalian-circadian-clock-2eit3xco.pdf

Inputs and Outputs of the Mammalian Circadian Clock

The evolution of Big Data in neuroscience and neurology

The suprachiasmatic nucleus (SCN) is composed of functionally distinct subpopulations of GABAergic neurons which form a neural network responsible for synchronizing most physiological and behavioral circadian rhythms in mammals. To date, little is known regarding which aspects of SCN rhythmicity are generated by individual SCN neurons, and which aspects result from neuronal interaction within a network. Here, we utilize in vivo miniaturized microscopy to measure fluorescent GCaMP-reported calcium dynamics in arginine vasopressin (AVP)-expressing neurons in the intact SCN of awake, behaving mice. We report that SCN AVP neurons exhibit periodic, slow calcium waves which we demonstrate, using in vivo electrical recordings, likely reflect burst firing. Further, we observe substantial heterogeneity of function in that AVP neurons exhibit unstable rhythms, and relatively weak rhythmicity at the population level. Network analysis reveals that correlated cellular behavior, or coherence, among neuron pairs also exhibited stochastic rhythms with about 33% of pairs rhythmic at any time. Unlike single-cell variables, coherence exhibited a strong rhythm at the population level with time of maximal coherence among AVP neuronal pairs at CT/ZT 6 and 9, coinciding with the timing of maximal neuronal activity for the SCN as a whole. These results demonstrate robust circadian variation in the coordination between stochastically rhythmic neurons and that interactions between AVP neurons in the SCN may be more influential than single-cell activity in the regulation of circadian rhythms. Furthermore, they demonstrate that cells in this circuit, like those in many other circuits, exhibit profound heterogenicity of function over time and space. 

Arginine–vasopressin-expressing neurons in the murine suprachiasmatic nucleus exhibit a circadian rhythm in network coherence in vivo

http://www.cell.com/article/S2589004222009671/pdf

Ontogeny of cellular organization and LGR5 expression in porcine cochlea revealed using tissue clearing and 3D imaging

Substance use disorder (SUD) is associated with severe health and social consequences. Continued drug use results in alterations of circuits within the mesolimbic dopamine system. It is critical to observe longitudinal impacts of SUD on neural activity in vivo to identify SUD predispositions, develop pharmaceuticals to prevent overdose, and help people suffering from SUD. However, implicated SUD associated areas are buried in deep brain which makes in vivo observation of neural activity challenging. The gradient index (GRIN) lens can probe these regions in mice and rats. In this short communications review, we will discuss how the GRIN lens can be coupled with other technologies such as miniaturized microscopes, fiberscopes, fMRI, and optogenetics to fully explore in vivo SUD research. Particularly, GRIN lens allows in vivo observation of deep brain regions implicated in SUD, differentiation of genetically distinct neurons, examination of individual cells longitudinally, correlation of neuronal patters with SUD behavior, and manipulation of neural circuits. 

GRIN lens applications for studying neurobiology of substance use disorder.

Light-guided sectioning for precise in situ localization and tissue interface analysis for brain-implanted optical fibers and GRIN lenses

Dorsal Excitor motor neuron DE-3 in the medicinal leech plays three very different dynamical roles in three different behaviors. Without rewiring its anatomical connectivity, how can a motor neuron dynamically switch roles to play appropriate roles in various behaviors? We previously used voltage-sensitive dye imaging to record from DE-3 and most other neurons in the leech segmental ganglion during (fictive) swimming, crawling, and local-bend escape (Tomina and Wagenaar, 2017). Here, we repeated that experiment, then re-imaged the same ganglion using serial blockface electron microscopy and traced DE-3's processes. Further, we traced back the processes of DE-3's presynaptic partners to their respective somata. This allowed us to analyze the relationship between circuit anatomy and the activity patterns it sustains. We found that input synapses important for all the behaviors were widely distributed over DE-3's branches, yet that functional clusters were different during (fictive) swimming vs. crawling.

Anatomy and activity patterns in a multifunctional motor neuron and its surrounding circuits.

Immediate Responses to Ambient Light in the Suprachiasmatic Nucleus Reveal Distinct Activity Profiles and Retinal Connectivity for SCN VIP Neurons

Adaptive social behavior enables an animal to distinguish threat-associated from safety-associated conspecifics. Failure to make this distinction may lead to social withdrawal and social anxiety, prominent symptoms of several neuropsychiatric disorders (Lissek et al., 2008, 2014; Beckers et al., 2023; Li et al., 2023). Although recent progress has been made in identifying the neural circuits underlying social memory behaviors that distinguish a familiar from novel conspecific (Hitti and Siegelbaum, 2014; Stevenson and Caldwell, 2014; Smith et al., 2016; Wu et al., 2021), the neural mechanisms that enable social memory for the discrimination of individuals based on past aversive experiences remain unknown (Padilla-Coreano et al., 2022). Here, we used a social fear conditioning paradigm that induced in both sexes robust behavioral discrimination of a conspecific associated with a footshock (CS+) from a non-reinforced interaction partner (CS-). Strikingly, chemogenetic or optogenetic silencing of hippocampal CA2 pyramidal neurons, which have been previously implicated in social novelty recognition memory, resulted in generalized avoidance fear behavior towards both the CS- and CS+. One-photon calcium imaging revealed that the accuracy with which CA2 representations discriminate the CS+ from the CS- animal was enhanced following social fear conditioning. Moreover the CA2 representations incorporated a generalized or abstract representation of social valence irrespective of conspecific identity and location. Thus, our results demonstrate, for the first time, that the same hippocampal CA2 subregion mediates social memories based on conspecific familiarity and social threat, through the incorporation of a representation of social valence into an initial representation of social identity.

/pdf/a-neural-mechanism-for-discriminating-threatening-from-safe-rfzkqrb6.pdf

A neural mechanism for discriminating threatening from safe social experiences

Perception and adaptive decision making rely on the integration of incoming sensory input with prior knowledge or expectations. While tactile stimuli play a significant role in shaping our perception and decision making, if and how prior information modulates the representation of tactile stimuli in early somatosensory cortices is largely unknown. Here, we employed functional magnetic resonance imaging (fMRI) and a vibrotactile detection paradigm to study the effect of prior information on tactile perception and tactile stimulus representation in early somatosensory areas. The supra-voxel somatotopic organization of early somatosensory areas allowed us to assess the effect of prior information on finger-specific representations. We found that vibrotactile stimuli congruent with expectations are associated with improved vibrotactile detection performance and a decrease of the mean blood-oxygen-level-dependent (BOLD) signal in the contralateral primary somatosensory cortex (S1). Concurrently, finger-specific activity associated with anticipated vibrotactile stimulation revealed higher multivariate decoding accuracies and better alignment with S1’s somatotopic organization. In addition, we observed that prior information induced somatotopically organized activity in contralateral S1 even before tactile stimulation onset. The accuracy of the multivariate decoding of stimulus-specific expectations was therefore strongly associated with upcoming behavioral detection performance. Thus, our results reveal a role for S1 in the integration of upcoming tactile stimuli with prior information based on its somatotopic organization as well as the presence of behaviorally relevant activity in S1 before stimulation onset.

/pdf/prior-information-enhances-tactile-representation-in-primary-dvl8f3te.pdf

Prior information enhances tactile representation in primary somatosensory cortex

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Light-guided sectioning for precise in situ localization and tissue interface analysis for brain-implanted optical fibers and GRIN lenses

Anatomy and activity patterns in a multifunctional motor neuron and its surrounding circuits.

Immediate Responses to Ambient Light in the Suprachiasmatic Nucleus Reveal Distinct Activity Profiles and Retinal Connectivity for SCN VIP Neurons

A neural mechanism for discriminating threatening from safe social experiences

Prior information enhances tactile representation in primary somatosensory cortex