Devsmita Das

The role of NMDA receptors in the pathophysiology and treatment of mood disorders.

Mood disorders such as major depressive disorder and bipolar disorder are chronic and recurrent illnesses that cause significant disability and affect approximately 350 million people worldwide. Currently available biogenic amine treatments provide relief for many and yet fail to ameliorate symptoms for others, highlighting the need to diversify the search for new therapeutic strategies. Here we present recent evidence implicating the role of N-methyl-D-aspartate receptor (NMDAR) signaling in the pathophysiology of mood disorders. The possible role of NMDARs in mood disorders has been supported by evidence demonstrating that: (i) both BPD and MDD are characterized by altered levels of central excitatory neurotransmitters; (ii) NMDAR expression, distribution, and function are atypical in patients with mood disorders; (iii) NMDAR modulators show positive therapeutic effects in BPD and MDD patients; and (iv) conventional antidepressants/mood stabilizers can modulate NMDAR function. Taken together, this evidence suggests the NMDAR system holds considerable promise as a therapeutic target for developing next generation drugs that may provide more rapid onset relief of symptoms. Identifying the subcircuits involved in mood and elucidating the role of NMDARs subtypes in specific brain circuits would constitute an important step toward the development of more effective therapies with fewer side effects.

Noradrenergic System in Down Syndrome and Alzheimer's Disease A Target for Therapy.

Locus coeruleus (LC) neurons in the brainstem send extensive noradrenergic (NE)-ergic terminals to the majority of brain regions, particularly those involved in cognitive function. Both Alzheimers disease (AD) and Down syndrome (DS) are characterized by similar pathology including significant LC degeneration and dysfunction of the NE-ergic system. Extensive loss of NE-ergic terminals has been linked to alterations in brain regions vital for cognition, mood, and executive function. While the mechanisms by which NE-ergic abnormalities contribute to cognitive dysfunction are not fully understood, emergent evidence suggests that rescue of NE-ergic system can attenuate neuropathology and cognitive decline in both AD and DS. Therapeutic strategies to enhance NE neurotransmission have undergone limited testing. Among those deployed to date are NE reuptake inhibitors, presynaptic α-adrenergic receptor antagonists, NE prodrugs, and β-adrenergic agonists. Here we examine alterations in the NE-ergic system in AD and DS and suggest that NE-ergic system rescue is a plausible treatment strategy for targeting cognitive decline in both disorders.

Nest building is impaired in the Ts65Dn mouse model of Down syndrome and rescued by blocking 5HT2a receptors.

Down syndrome (DS) has an incidence of about 1/700 births, and is therefore the most common cause of cognitive and behavioral impairments in children. Recent studies on mouse models of DS indicate that a number of pharmacotherapies could be beneficial for restoring cognitive abilities in individuals with DS. Attention deficits that are present in DS account in part for learning and memory deficiencies yet have been scarcely studied in corresponding models. Investigations of this relevant group of behaviors is more difficult in mouse models because of the difficulty in homologizing mouse and human behaviors and because standard laboratory environments do not always elicit behaviors of interest. Here we characterize nest building as a goal-directed behavior that is seriously impaired in young Ts65Dn mice, a genetic model of DS. We believe this impairment may reflect in part attention deficits, and we investigate the physiological, genetic, and pharmacological factors influencing its expression. Nesting behavior in young Ts65Dn mice was severely impaired when the animals were placed in a novel environment. But this context-dependent impairment was transient and reversible. The genetic determinants of this deficiency are restricted to a ∼100 gene segment on the murine chromosome 16. Nest building behavior is a highly integrated phenotypic trait that relies in part on limbic circuitry and on the frontal cortex in relation to cognitive and attention processes. We show that both serotonin content and 5HT2a receptors are increased in the frontal cortex of Ts65Dn mice and that pharmacological blockage of 5HT2a receptors in Ts65Dn mice rescues their context dependent nest building impairment. We propose that the nest-building trait could represent a marker of attention related deficits in DS models and could be of value in designing pharmacotherapies for this specific aspect of DS. 5HT2a modulation may improve goal-directed behavior in DS.

Neurotransmitter-based strategies for the treatment of cognitive dysfunction in Down syndrome.

Down syndrome (DS) is a multisystem disorder affecting the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic, and musculoskeletal systems and is characterized by significant cognitive disability and a possible common pathogenic mechanism with Alzheimers disease. During the last decade, numerous studies have supported the notion that the triplication of specific genes on human chromosome 21 plays a significant role in cognitive dysfunction in DS. Here we reviewed studies in trisomic mouse models and humans, including children and adults with DS. In order to identify groups of genes that contribute to cognitive disability in DS, multiple mouse models of DS with segmental trisomy have been generated. Over-expression of these particular genes in DS can lead to dysfunction of several neurotransmitter systems. Therapeutic strategies for DS have either focused on normalizing the expression of triplicated genes with important roles in DS or restoring the function of these systems. Indeed, our extensive review of studies on the pathogenesis of DS suggests that one plausible strategy for the treatment of cognitive dysfunction is to target the cholinergic, serotonergic, GABA-ergic, glutamatergic, and norepinephrinergic system. However, a fundamental strategy for treatment of cognitive dysfunction in DS would include reducing to normal levels the expression of specific triplicated genes in affected systems before the onset of neurodegeneration.

Assessment of dendritic arborization in the dentate gyrus of the hippocampal region in mice.

Dendritic arborization has been shown to be a reliable marker for examination of structural and functional integrity of neurons. Indeed, the complexity and extent of dendritic arborization correlates well with the synaptic plasticity in these cells. A reliable method for assessment of dendritic arborization is needed to characterize the deleterious effects of neurological disorders on these structures and to determine the effects of therapeutic interventions. However, quantification of these structures has proven to be a formidable task given their complex and dynamic nature. Fortunately, sophisticated imaging techniques can be paired with conventional staining methods to assess the state of dendritic arborization, providing a more reliable and expeditious means of assessment. Below is an example of how these imaging techniques were paired with staining methods to characterize the dendritic arborization in wild type mice. These complementary imaging methods can be used to qualitatively and quantitatively assess dendritic arborization that span a rather wide area within the hippocampal region.

Increased incidence of intermittent hypoxemia in the Ts65Dn mouse model of Down syndrome

In addition to nervous system, cardiovascular and respiratory systems are primarily affected in Down syndrome (DS). The Ts65Dn mouse model is widely used to recapitulate cognitive dysfunction in DS. While these mice consistently show failure in learning and memory along with functional and structural abnormalities in the hippocampal region, the underlying mechanisms behind cognitive dysfunction remain to be fully elucidated. Convergent evidence implicates chronic episodes of hypoxemia in cognitive dysfunction in people with DS. Using an infra-red detection system to assess oxygen saturation in free-moving mice, we assessed arterial blood oxygenation in both adolescent and adult Ts65Dn mice and found a significant increase in the incidence of hypoxemia in both groups. Notably, the severity of hypoxemia increased during the dark cycle, suggesting a link between hypoxemia and increased motor activity. Postmortem analysis showed significant increase in the expression of mitochondrial Cox4i2, the terminal enzyme of the mitochondrial respiratory chain and oxygen response element. Altogether these data suggest early and chronic occurrence of hypoxemia in the Ts65Dn mouse model of DS, which can contribute to cognitive dysfunction in these mice.

PET/MRI in Brain Tumors

Neuroimaging plays a decisive role in the complex scenario of brain tumors management. Molecular imaging with positron emission tomography (PET) and the new advanced magnetic resonance imaging (MRI) techniques, permits noninvasive tumor characterization, and a more targeted therapeutic approach, with the goal of ultimately improving prognosis. While MRI remains the mainstay technique for brain tumors imaging, PET aids complementing MRI in addressing those questions that remain unanswered, such as lesion grading, tumor extent delineation and treatment response evaluation, amongst the many. The novel hybrid PET/MRI system, combining the strengths of both imaging techniques, allows us to obtain structural, functional and molecular information of brain tumors in one single scan. This chapter will review the main features of different MR techniques and PET radiopharmaceuticals used in brain tumors imaging, describing in detail also the current applications of integrated PET/MRI systems and the advantages of the combined approach.

Eponymous ‘Valves' of the Nasolacrimal Drainage Apparatus: I. A Historical Review: ‘Valves' of the Nasolacrimal Drainage Apparatus

The nasolacrimal drainage apparatus (NDA) is of interest to anatomists, radiologists, and ophthalmologists alike, owing to its intricate luminal contour, complex surrounding structural morphology, and its clinical relevance. Here, we review the history of anatomical descriptions of so‐called luminal “valves” of the NDA, including the numerous historical figures whose eponyms adorn the NDA. By 1908, multiple false “valves” that are likely no more than mounds of mucosa along the NDA had been recorded. In the modern era, these have all been largely considered speculative in nature and function aside from the consistently described true valve of Hasner (plica lacrimalis). Back then, eight so‐called “valves” were believed to be identifiable. These were the “valves” of Foltz, Bochdalek, Rosenmüller, Huschke, Aubaret, Béraud or Krause, Taillefer, and Hasner or Cruveilhier or Bianchi. With the advent of detailed characterization through modern high‐resolution imaging techniques, such as digital subtraction dacryocystography (DS‐DCG), many of these valvular folds have come into question owing to their inconsistent identification. This historical review should be useful for greater understanding and accurate contextual interpretation of “valves” encountered on DS‐DCG studies, and in clinical management and therapeutic planning of patients prior to undergoing luminal procedures on the NDA. Clin. Anat., 2018.

Eponymous ‘Valves' of the Nasolacrimal Drainage Apparatus: II. Frequency of Visualization on Dacryocystography: ‘Valves' of the Nasolacrimal Drainage Apparatus

Developmental remnants may follow segmental canalization of ectodermal epithelial cords forming the nasolacrimal drainage apparatus (NDA). This can result in false luminal “valves” along the path of the NDA, many of which have been named, but most have not been anatomically identified with consistency. By 1908, eight such “valves” were documented, those of: Foltz, Bochdalek, Rosenmüller, Huschke, Aubaret, Béraud or Krause, Taillefer, and Hasner or Cruveilhier or Bianchi. Digital subtraction dacryocystography (DS‐DCG) is the highest spatial resolution imaging technique available to outline in vivo NDA anatomy, luminal profile, and pathology. We believe this is the first report of the conspicuousness and frequency of these “valves” on DS‐DCG. We retrospectively analyzed routine DS‐DCGs with normal findings for the presence and frequency of the eight NDA “valves.” We examined 92 normal DS‐DCGs on patients aged 14–82 years (71% female, 29% male). We observed “valves” most reliably in the inferior nasolacrimal duct: the inferior valve of Hasner (plica lacrimalis) was present in 98.9% of cases, and more superiorly, the valve of Taillefer (93.5%) and the valve of Krause (79.3%). Contrastingly, we infrequently identified the very superior “valves”: Foltz or Bochdalek in 17.1%, Rosenmüller or Huschke in 46.4%, and Auberat in 40% of cases. Therefore, unlike the inferior NDA valves, these more superior “valves” were less consistently identified and are presumed to be simple mural mucosal irregularities rather than true structural valves. These findings will be useful in diagnostic interpretation of DS‐DCGs and therapeutic planning for patients undergoing luminal procedures on the NDA. Clin. Anat., 2018.