Gregory W. Kirschen

Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function

Significance In humans, obesity impairs cognition and produces atrophy of brain regions associated with learning and memory, but few studies have investigated the underlying cellular mechanisms. We used a diet-induced model of obesity in rats to study excessive weight gain and found that early stage obesity, before the onset of diabetes or metabolic syndrome, produced deficits on cognitive tasks that require the prefrontal cortex. Impaired cognition was associated with synapse loss, including reduced numbers of dendritic spines and expression of synaptic proteins, as well as structural alterations in the brain’s immune cells, the microglia. These results strongly suggest that obesity must be considered as a contributing factor to brain dysfunction, with implications for its increasing frequency in contemporary western society. Obesity is a major public health problem affecting overall physical and emotional well-being. Despite compelling data suggesting an association between obesity and cognitive dysfunction, this phenomenon has received relatively little attention. Neuroimaging studies in obese humans report reduced size of brain regions involved in cognition, but few studies have investigated the cellular processes underlying cognitive decline in obesity or the influence of obesity on cognition in the absence of obesity-related illnesses. Here, a rat model of diet-induced obesity was used to explore changes in brain regions important for cognition. Obese rats showed deficits on cognitive tasks requiring the prefrontal and perirhinal cortex. Cognitive deficits were accompanied by decreased dendritic spine density and synaptic marker expression in both brain regions. Microglial morphology was also changed in the prefrontal cortex. Detrimental changes in the prefrontal cortex and perirhinal cortex occurred before metabolic syndrome or diabetes, suggesting that these brain regions may be particularly vulnerable to early stage obesity.

Active dentate granule cells encode experience to promote the addition of adult-born hippocampal neurons

The continuous addition of new dentate granule cells (DGCs), which is regulated exquisitely by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to affect the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca2+ imaging to track the real-time activity of individual DGCs in freely behaving mice. For the first time, we found that active DGCs responded to a novel experience by increasing their Ca2+ event frequency preferentially. This elevated activity, which we found to be associated with object exploration, returned to baseline by 1 h in the same environment, but could be dishabituated via introduction to a novel environment. To transition seamlessly between environments, we next established a freely controllable virtual reality system for unrestrained mice. We again observed increased firing of active neurons in a virtual enriched environment. Interestingly, multiple novel virtual experiences increased the number of newborn neurons accumulatively compared with a single experience. Finally, optogenetic silencing of existing DGCs during novel environmental exploration perturbed experience-induced neuronal addition. Our study shows that the adult brain conveys novel, enriched experiences to increase the addition of adult-born hippocampal neurons by increasing the firing of active DGCs. SIGNIFICANCE STATEMENT Adult brains are constantly reshaping themselves from synapses to circuits as we encounter novel experiences from moment to moment. Importantly, this reshaping includes the addition of newborn hippocampal neurons. However, it remains largely unknown how our circuits encode experience-induced brain activity to govern the addition of new hippocampal neurons. By coupling in vivo Ca2+ imaging of dentate granule neurons with a novel, unrestrained virtual reality system for rodents, we discovered that a new experience increased firing of active dentate granule neurons rapidly and robustly. Exploration in multiple novel virtual environments, compared with a single environment, promoted dentate activation and enhanced the addition of new hippocampal neurons accumulatively. Finally, silencing this activation optogenetically during novel experiences perturbed experience-induced neuronal addition.

Chapter 2 – Physiology and Plasticity

Every day, thousands of new dentate granule cells (DGCs) are born in the subgranular zone (SGZ) of the dentate gyrus (DG), wherein a niche of neuronal precursors undergoes continuous division and differentiation throughout mammalian life. Yet, only a fraction of these cells will ultimately survive and mature to become functional members of the DG neuronal population. Newborn DGCs form early excitatory GABAergic and later excitatory glutamatergic synapses as they join the functional architecture of the DG. In addition, newborn cells are more plastic than mature ones, likely helping younger cells to form connections and contribute meaningfully to hippocampal function. What processes regulate the fate of newborn DGCs, how do they integrate into the existing neuronal circuitry of the hippocampus, and what are the physiological/behavioral roles of DG plasticity? Here we review the current evidence, largely based on studies in rodents and nonhuman primates.

Youth Screen Media Habits and Sleep: Sleep-Friendly Screen Behavior Recommendations for Clinicians, Educators, and Parents

With the widespread use of portable electronic devices and the normalization of screen media devices in the bedroom, insufficient sleep has become commonplace. In a recent literature review, 90% of included studies found an association between screen media use and delayed bedtime and/or decreased total sleep time. This pervasive phenomenon of pediatric sleep loss has widespread implications. There is a need for basic, translational, and clinical research examining the effects of screen media on sleep loss and health consequences in children and adolescents to educate and motivate clinicians, teachers, parents and youth themselves to foster healthy sleep habits.

Depletion of primary cilia from mature dentate granule cells impairs hippocampus-dependent contextual memory.

The primary cilium, a sensory organelle, regulates cell proliferation and neuronal development of dentate granule cells in the hippocampus. However, its role in the function of mature dentate granule cells remains unknown. Here we specifically depleted and disrupted ciliary proteins IFT20 and Kif3A (respectively) in mature dentate granule cells and investigated hippocampus-dependent contextual memory and long-term plasticity at mossy fiber synapses. We found that depletion of IFT20 in these cells significantly impaired context-dependent fear-related memory. Furthermore, we tested synaptic plasticity of mossy fiber synapses in area CA3 and found increased long-term potentiation upon depletion of IFT20 or disruption of Kif3A. Our findings suggest a role of primary cilia in the memory function of mature dentate granule cells, which may result from abnormal mossy fiber synaptic plasticity. A direct link between the primary cilia of mature dentate granule cells and behavior will require further investigation using independent approaches to manipulate primary cilia.

Genetic dissection of the neuro-glio-vascular machinery in the adult brain

The adult brain actively controls its metabolic homeostasis via the circulatory system at the blood brain barrier interface. The mechanisms underlying the functional coupling from neuron to vessel remain poorly understood. Here, we established a novel method to genetically isolate the individual components of this coupling machinery using a combination of viral vectors. We first discovered a surprising non-uniformity of the glio-vascular structure in different brain regions. We carried out a viral injection screen and found that intravenous Canine Adenovirus 2 (CAV2) preferentially targeted perivascular astrocytes throughout the adult brain, with sparing of the hippocampal hilus from infection. Using this new intravenous method to target astrocytes, we selectively ablated these cells and observed severe defects in hippocampus-dependent contextual memory and the metabolically regulated process of hippocampal neurogenesis. Combined with AAV9 targeting of neurons and endothelial cells, all components of the neuro-glio-vascular machinery can be simultaneously labeled for genetic manipulation. Together, we demonstrate a novel method, which we term CATNAP (CAV/AAV Targeting of Neurons and Astrocytes Perivascularly), to target and manipulate the neuro-glio-vascular machinery in the adult brain.

Structural Plasticity Induced by Adult Neurogenesis

Memory formation, storage, and retrieval are computationally demanding tasks. To handle this problem, the mammalian brain has developed a form of metaplasticity, whereby new neurons are continuously generated and integrated into preexisting networks to support ongoing information processing throughout life. In particular, neurogenesis in adulthood affects the synaptic landscape of the dentate gyrus (DG) of the hippocampus and the olfactory bulb (OB), where new neurons establish connections with existing cells and contribute to the proper functioning of the circuits. Here we review the current evidence on the structural plasticity of adult-generated neurons and how this relates to the plasticity of the preexisting networks that they modulate, focusing largely on rodent hippocampal neurogenesis, with comparisons drawn to OB neurogenesis. Neurogenesis-induced rewiring occurs in a manner that permits the functional integration of new neurons while maintaining a balance of activity by recruiting inhibitory interneuron networks in the case of the DG, or by directly modulating sensory input and principal neuron output in the case of the OB. As our understanding of these continuously rewiring networks evolves, we expect that computational models will grow in tandem to provide increasingly accurate predictions, and will lead us to ask more informed questions about the nature of these complex information processing systems.

Repositioning of Somatic Golgi Apparatus Is Essential for the Dendritic Establishment of Adult-Born Hippocampal Neurons

New dentate granule cells (DGCs) are continuously generated, and integrate into the preexisting hippocampal network in the adult brain. How an adult-born neuron with initially simple spindle-like morphology develops into a DGC, consisting of a single apical dendrite with further branches, remains largely unknown. Here, using retroviruses to birth date and manipulate newborn neurons, we examined initial dendritic formation and possible underlying mechanisms. We found that GFP-expressing newborn cells began to establish a DGC-like morphology at ∼7 d after birth, with a primary dendrite pointing to the molecular layer, but at this stage, with several neurites in the neurogenic zone. Interestingly, the Golgi apparatus, an essential organelle for neurite growth and maintenance, was dynamically repositioning in the soma of newborn cells during this initial integration stage. Two weeks after birth, by which time most neurites in the neurogenic zone were eliminated, a compact Golgi apparatus was positioned exclusively at the base of the primary dendrite. We analyzed the presence of Golgi-associated genes using single-cell transcriptomes of newborn DGCs, and among Golgi-related genes, found the presence of STK25 and STRAD, regulators of embryonic neuronal development. When we knocked down either of these two proteins, we found Golgi mislocalization and extensive aberrant dendrite formation. Furthermore, overexpression of a mutated form of STRAD, underlying the disorder polyhydramnios, megalencephaly, and symptomatic epilepsy, characterized by abnormal brain development and intractable epilepsy, caused similar defects in Golgi localization and dendrite formation in adult-born neurons. Together, our findings reveal a role for Golgi repositioning in regulating the initial integration of adult-born DGCs. SIGNIFICANCE STATEMENT Since the discovery of the continuous generation of new neurons in the adult hippocampus, extensive effort was directed toward understanding the functional contribution of these newborn neurons to the existing hippocampal circuit and associated behaviors, while the molecular mechanisms controlling their early morphological integration are less well understood. Dentate granule cells (DGCs) have a single, complex, apical dendrite. The events leading adult-born DGCs to transition from simple spindle-like morphology to mature dendrite morphology are largely unknown. We studied establishment of newborn DGCs dendritic pattern and found it was mediated by a signaling pathway regulating precise localization of the Golgi apparatus. Furthermore, this Golgi-associated mechanism for dendrite establishment might be impaired in a human genetic epilepsy syndrome, polyhydramnios, megalencephaly, and symptomatic epilepsy.

Probability of viral labeling of neural stem cells in vivo

In the neuroscience field over the past several decades, viral vectors have become powerful gene delivery systems to study neural populations of interest. For neural stem cell (NSC) biology, such viruses are often used to birth-date and track NSCs over developmental time in lineage tracing experiments. Yet, the probability of successful infection of a given stem cell in vivo remains unknown. This information would be helpful to inform investigators interested in titrating their viruses to selectively target sparsely-populated clusters of cells in the nervous system. Here, we describe a novel approach to calculate the probability of successful viral infection of NSCs using experimentally-derived cell cluster data from our newly-developed method to sparsely label adult NSCs, and a simple statistical derivation. Others interested in precisely defining their viral infection efficiency can use this method for a variety of basic and translational studies.

Betrayal of the Body: Group Approaches to Hypo-Sexuality for Adult Female Sufferers of Childhood Sexual Abuse

ABSTRACT Hypo-sexuality, self-reported hypoactive sexual desire and/or sexual aversion, is a common symptom experienced by women who were victims of childhood sexual abuse. This symptom may be distressing to the patient herself, and may place strain on her romantic relationships in adulthood. Unfortunately, this problem often remains undiscussed between patient and provider, in part due to the provider’s lack of comfort or knowledge regarding how best to address this issue. In this article, we explore several strategies that providers may employ in a group setting in order to help women realize their sexuality while minimizing untoward side effects such as feelings of guilt or shame, or flashbacks. We highlight the merits of each technique, and provide insights from clinical experience to guide practitioners to help their patients facing this difficult issue.