Humor Modulates the Mesolimbic Reward Centers

AbstractHumor plays an essential role in many facets of human life including psychological, social, and somatic functioning. Recently, neuroimaging has been applied to this critical human attribute, shedding light on the affective, cognitive, and motor networks involved in humor processing. To date, however, researchers have failed to demonstrate the subcortical correlates of the most fundamental feature of humor—reward. In an effort to elucidate the neurobiological substrate that subserves the reward components of humor, we undertook a high-field (3 Tesla) event-related functional MRI study. Here we demonstrate that humor modulates activity in several cortical regions, and we present new evidence that humor engages a network of subcortical regions including the nucleus accumbens, a key component of the mesolimbic dopaminergic reward system. Further, the degree of humor intensity was positively correlated with BOLD signal intensity in these regions. Together, these findings offer new insight into the neural basis of salutary aspects of humor

Molecular controls over neocortical neuronal diversity and oligodendrocyte development

Much of the remarkable processing capacity of the neocortex lies in the precisely orchestrated generation of diverse neuronal subtypes. Heterogeneous glial populations must subsequently be generated to ensure that neurons function and communicate appropriately. An emerging understanding of neocortical development has revealed at least two major molecular transitions that establish neuronal and glial heterogeneity. The first involves the spatial molecular parcellation of dorsal (pallial) progenitors that generate excitatory long-distance cortical projection neurons, from ventral (subpallial) progenitors that generate inhibitory locally-projecting cortical interneurons. Postmitotic molecular programs that also differ between pallial and subpallial domains then ensure that neurons differentiate appropriately. The second transition involves the temporal parcellation of early molecular regulators that drive neurogenesis from later regulators that drive gliogenesis within the same proliferative domains. While much progress has been made in characterizing broad aspects of forebrain development, many of the molecular controls responsible for precisely generating distinct neuronal subtypes and their glial counterparts remain unknown. In this dissertation, I characterize multiple functions of the highly related transcriptional regulators SOX6 and SOX5 during neocortical progenitor, excitatory neuron, inhibitory neuron, and oligodendrocyte development. In striking contrast to their overlapping expression and functions in other systems, in the forebrain, SOX6 and SOX5 are mutually exclusively expressed with distinct, complementary functions. Using loss- and gain-of-function, molecular, morphological, anatomical, and microarray analyses, I found that: (1) SOX6 controls the dorsal identity of pallial progenitors by repressing subpallial molecular programs; (2) SOX5 postmitotically regulates the sequential generation of distinct excitatory projection neuron subtypes, ensuring cortical projection neuron diversity. Relatedly, I found that the molecular identity of cortical neuron subtypes is only gradually refined, indicating that postmitotic regulators such as SOX5 are essential to execute appropriate subtype differentiation; (3) SOX6 functions postmitotically in the parallel population of inhibitory cortical interneurons, controlling their differentiation and subtype diversity; and (4) SOX6 regulates myelinating oligodendrocyte development, in part by repressing neurogenic cues after the transition to oligodendrogliogenesis. Taken together, these analyses demonstrate multiple complementary functions of SOX6 and SOX5 across distinct neural cell types, revealing the parsimonious use of transcriptional regulators in diverse contexts during neocortical development and evolution

Direct and indirect spino-cerebellar pathways : shared ideas but different functions in motor control

The impressive precision of mammalian limb movements relies on internal feedback pathways that convey information about ongoing motor output to cerebellar circuits. The spino-cerebellar tracts (SCT) in the cervical, thoracic and lumbar spinal cord have long been considered canonical neural substrates for the conveyance of internal feedback signals. Here we consider the distinct features of an indirect spino-cerebellar route, via the brainstem lateral reticular nucleus (LRN), and the implications of this pre-cerebellar "detour" for the execution and evolution of limb motor control. Both direct and indirect spino-cerebellar pathways signal spinal interneuronal activity to the cerebellum during movements, but evidence suggests that direct SCT neurons are mainly modulated by rhythmic activity, whereas the LRN also receives information from systems active during postural adjustment, reaching and grasping. Thus, while direct and indirect spinocerebellar circuits can both be regarded as internal copy pathways, it seems likely that the direct system is principally dedicated to rhythmic motor acts like locomotion, while the indirect system also provides a means of pre-cerebellar integration relevant to the execution and coordination of dexterous limb movements

The cerebellar nuclei and dexterous limb movements

Dexterous forelimb movements like reaching, grasping, and manipulating objects are fundamental building blocks of the mammalian motor repertoire. These behaviors are essential to everyday activities, and their elaboration underlies incredible accomplishments by human beings in art and sport. Moreover, the susceptibility of these behaviors to damage and disease of the nervous system can lead to debilitating deficits, highlighting a need for a better understanding of function and dysfunction in sensorimotor control. The cerebellum is central to coordinating limb movements, as defined in large part by Joseph Babinski and Gordon Holmes describing motor impairment in patients with cerebellar lesions over 100 years ago (Babinski, 1902; Holmes, 1917), and supported by many important human and animal studies that have been conducted since. Here, with a focus on output pathways of the cerebellar nuclei across mammalian species, we describe forelimb movement deficits observed when cerebellar circuits are perturbed, the mechanisms through which these circuits influence motor output, and key challenges in defining how the cerebellum refines limb movement.Ministry of Education (MOE)A.I.C. was supported by Singapore Ministry of Education Tier 2 (MOE2018T2-1-065) and Tier 3 (MOE2017-T3-1-002). E.A. was supported by the National Institutes of Health (DP2NS105555, R01NS111479, and U19NS112959), the Searle Scholars Program, The Pew Charitable Trusts, and the McKnight Foundation

Direct and indirect spino-cerebellar pathways : shared ideas but different functions in motor control

The impressive precision of mammalian limb movements relies on internal feedback pathways that convey information about ongoing motor output to cerebellar circuits. The spino-cerebellar tracts (SCT) in the cervical, thoracic and lumbar spinal cord have long been considered canonical neural substrates for the conveyance of internal feedback signals. Here we consider the distinct features of an indirect spino-cerebellar route, via the brainstem lateral reticular nucleus (LRN), and the implications of this pre-cerebellar "detour" for the execution and evolution of limb motor control. Both direct and indirect spino-cerebellar pathways signal spinal interneuronal activity to the cerebellum during movements, but evidence suggests that direct SCT neurons are mainly modulated by rhythmic activity, whereas the LRN also receives information from systems active during postural adjustment, reaching and grasping. Thus, while direct and indirect spinocerebellar circuits can both be regarded as internal copy pathways, it seems likely that the direct system is principally dedicated to rhythmic motor acts like locomotion, while the indirect system also provides a means of pre-cerebellar integration relevant to the execution and coordination of dexterous limb movements

Large-scale capture of hidden fluorescent labels for training generalizable markerless motion capture models

Abstract Deep learning-based markerless tracking has revolutionized studies of animal behavior. Yet the generalizability of trained models tends to be limited, as new training data typically needs to be generated manually for each setup or visual environment. With each model trained from scratch, researchers track distinct landmarks and analyze the resulting kinematic data in idiosyncratic ways. Moreover, due to inherent limitations in manual annotation, only a sparse set of landmarks are typically labeled. To address these issues, we developed an approach, which we term GlowTrack, for generating orders of magnitude more training data, enabling models that generalize across experimental contexts. We describe: a) a high-throughput approach for producing hidden labels using fluorescent markers; b) a multi-camera, multi-light setup for simulating diverse visual conditions; and c) a technique for labeling many landmarks in parallel, enabling dense tracking. These advances lay a foundation for standardized behavioral pipelines and more complete scrutiny of movement

SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development

The neuronal diversity of the CNS emerges largely from controlled spatial and temporal segregation of cell type-specific molecular regulators. We found that the transcription factor SOX6 controls the molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors and the differentiation of cortical interneurons, regulating forebrain progenitor and interneuron heterogeneity. During corticogenesis in mice, SOX6 and SOX5 were largely mutually exclusively expressed in pallial and subpallial progenitors, respectively, and remained mutually exclusive in a reverse pattern in postmitotic neuronal progeny. Loss of SOX6 from pallial progenitors caused their inappropriate expression of normally subpallium-restricted developmental controls, conferring mixed dorsal-ventral identity. In postmitotic cortical interneurons, loss of SOX6 disrupted the differentiation and diversity of cortical interneuron subtypes, analogous to SOX5 control over cortical projection neuron development. These data indicate that SOX6 is a central regulator of both progenitor and cortical interneuron diversity during neocortical development.Stem Cell and Regenerative Biolog