Search PubMed⌕ Search

Biomedical subjects

Patrick R Hof

Publications and source records attributed to Patrick R Hof.

At least 37 records · Page 2Linked to original sources
PubMed2005

Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress.

Apical dendritic retraction and axospinous synapse loss in the medial prefrontal cortex (PFC) are structural alterations that result from repeated restraint stress. Such changes in this brain region may be associated with impaired working memory, altered emotionality, and inability to regulate hypothalamic-pituitary adrenal activity, which in turn may underlie stress-related mental illnesses. In the present study, we examined the persistence of these stress-induced dendritic alterations in the medial PFC following the cessation of stress. Animals received either daily restraint stress for a 3-week period and were then allowed to recover for another 3 weeks, restraint stress for 3 or 6 weeks, or no restraint. Following perfusion and fixation, intracellular iontophoretic injections of Lucifer Yellow were performed in layer II/III pyramidal neurons in slices from the medial PFC, and apical and basal dendritic arbors were reconstructed in three dimensions. We observed a significant reduction in apical dendritic length and branch number following 3 or 6 weeks of repeated stress compared to 3-week stress/3-week recovery. These results suggest that stress-induced dendritic plasticity in the medial PFC is reversible and may have implications for the functional recovery of medial PFC function following prolonged psychological stress.

Animals↗
PubMed2005

Selective expression of presenilin 1 in neural progenitor cells rescues the cerebral hemorrhages and cortical lamination defects in presenilin 1-null mutant mice.

Mice with a null mutation of the presenilin 1 gene (Psen1(-/-)) die during late intrauterine life or shortly after birth and exhibit multiple CNS and non-CNS abnormalities, including cerebral hemorrhages and altered cortical development. The cellular and molecular basis for the developmental effects of Psen1 remain incompletely understood. Psen1 is expressed in neural progenitors in developing brain, as well as in postmitotic neurons. We crossed transgenic mice with either neuron-specific or neural progenitor-specific expression of Psen1 onto the Psen1(-/-) background. We show that neither neuron-specific nor neural progenitor-specific expression of Psen1 can rescue the embryonic lethality of the Psen1(-/-) embryo. Indeed neuron-specific expression rescued none of the abnormalities in Psen1(-/-) mice. However, Psen1 expression in neural progenitors rescued the cortical lamination defects, as well as the cerebral hemorrhages, and restored a normal vascular pattern in Psen1(-/-) embryos. Collectively, these studies demonstrate that Psen1 expression in neural progenitor cells is crucial for cortical development and reveal a novel role for neuroectodermal expression of Psen1 in development of the brain vasculature.

Animals↗
PubMed2005

Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms.

Mutations in the microtubule-associated protein tau gene have been linked to neurofibrillary tangle (NFT) formation in several neurodegenerative diseases known as tauopathies; however, no tau mutations occur in Alzheimer's disease, although this disease is also characterized by NFT formation and cell death. Importantly, the mechanism of tau-mediated neuronal death remains elusive. Aged mice expressing nonmutant human tau in the absence of mouse tau (htau mice) developed NFTs and extensive cell death. The mechanism of neuron death was investigated in htau mice, and surprisingly, the presence of tau filaments did not correlate directly with death within individual cells, suggesting that cell death can occur independently of NFT formation. Our observations show that the mechanism of neurodegeneration involved reexpression of cell-cycle proteins and DNA synthesis, indicating that nonmutant tau pathology and neurodegeneration may be linked via abnormal, incomplete cell-cycle reentry.

Aging↗
PubMed2005

Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex.

The prefrontal cortex (PFC) plays an important role in higher cognitive processes, and in the regulation of stress-induced hypothalamic-pituitary-adrenal (HPA) activity. Here we examined the effect of repeated restraint stress on dendritic spine number in the medial PFC. Rats were perfused after receiving 21 days of daily restraint stress, and intracellular iontophoretic injections of Lucifer Yellow were carried out in layer II/III pyramidal neurons in the anterior cingulate and prelimbic cortices. We found that stress results in a significant (16%) decrease in apical dendritic spine density in medial PFC pyramidal neurons, and confirmed a previous observation that total apical dendritic length is reduced by 20% in the same neurons. We estimate that nearly one-third of all axospinous synapses on apical dendrites of pyramidal neurons in medial PFC are lost following repeated stress. A decrease in medial PFC dendritic spines may not only be indicative of a decrease in the total population of axospinous synapses, but may impair these neurons' capacity for biochemical compartmentalization and plasticity in which dendritic spines play a major role. Dendritic atrophy and spine loss may be important cellular features of stress-related psychiatric disorders where the PFC is functionally impaired.

Animals↗
PubMed2005

Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia.

BACKGROUND AND PURPOSE: Most previous studies addressed the cognitive impact of lacunar infarcts using radiologic correlations that are known to correlate poorly with neuropathological data. Moreover, absence of systematic bilateral assessment of vascular lesions and masking effects of Alzheimer disease pathology and macrovascular lesions may explain discrepancies among previous reports. To define the relative contribution of silent lacunes to cognitive decline, we performed a detailed analysis of lacunar and microvascular pathology in both cortical and subcortical areas of 72 elderly individuals without significant neurofibrillary tangle pathology or macrovascular lesions. METHODS: Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included Abeta-protein deposition staging and bilateral assessment of microvascular ischemic pathology and lacunes; statistical analysis included multivariate models controlling for age, amyloid deposits, and microvascular pathology. RESULTS: Thalamic and basal ganglia lacunes were negatively associated with CDR scores; cortical microinfarcts, periventricular and diffuse white matter demyelination also significantly affected cognition. In a multivariate model, cortical microinfarcts and thalamic and basal ganglia lacunes explained 22% of CDR variability; amyloid deposits and microvascular pathology explained 12%, and the assessment of thalamic and basal ganglia lacunes added an extra 17%. Deep white matter lacunes were not related to cognitive status in univariate and multivariate models. CONCLUSIONS: In agreement with the recently proposed concept of subcortical ischemic vascular dementia, our autopsy series provides important evidence that gray matter lacunes are independent predictors of cognitive decline in elderly individuals without concomitant dementing processes such as Alzheimer disease.

Aged↗
PubMed2005

Stereological studies of capillary length density in the frontal cortex of schizophrenics.

The presence of microvasculature abnormalities in the prefrontal cortex of schizophrenics was proposed in a recent study of molecular signatures of schizophrenia [Prabakaran et al (2004) Mol Psychiat 9:684-697]. To assess this possibility further, we investigated capillary length densities in prefrontal cortex area 9 and anterior cingulate cortex area 24 in postmortem brains from 13 schizophrenics and 13 age- and sex-matched controls. To check that our sample of brains shared cardinal neuropathological features of schizophrenia with previously reported case studies, we also measured cortical gray matter volumes and cortical thickness in areas 9 and 24. The mean cortical gray matter volume was significantly reduced in brains from schizophrenics compared to controls. Mean cortical thickness was significantly reduced in area 24, but not in area 9, in schizophrenics. There were no differences in mean capillary length densities in either area 9 or 24 between the two groups. Thus, alterations in capillary length density in the prefrontal cortex cannot be considered a general feature of schizophrenia. Compromised brain metabolism and occurrence of oxidative stress in the brain of schizophrenics are likely caused by other mechanisms.

Adult↗
PubMed2005

Cognitive impact of neuronal pathology in the entorhinal cortex and CA1 field in Alzheimer's disease.

The relative contribution of Alzheimer's disease (AD) hippocampal neuronal pathology in cognitive decline is still a matter of debate. To address this issue, we performed a stereological analysis of layer II of the entorhinal cortex and the CA1 field of the hippocampus in 34 autopsy cases covering the whole spectrum of old age and Clinical Dementia Rating (CDR) scores. In both areas, the proportion of neurofibrillary tangle (NFT)-containing neurons increased steadily as a function of the CDR score. Questionable dementia was associated with a 1.9% neuronal loss in the entorhinal cortex and 26% in the CA1 field. NFT numbers predicted only 38% of the neuron number variability in the entorhinal cortex and 55% in the CA1 field. Neuron counts in the entorhinal cortex and both neuron and NFT counts in the CA1 field were significantly associated with cognitive status explaining 25% and 44% of the CDR variability, respectively. Our data reveal a dissociation between the patterns of progression of NFT and neuronal loss in the entorhinal cortex and CA1 field. Moreover, they show that less than 50% of the cognitive variability may be attributable to AD neuronal pathology in these areas.

Age Factors↗
PubMed2005

Fronto-thalamo-striatal gray and white matter volumes and anisotropy of their connections in bipolar spectrum illnesses.

BACKGROUND: Neurons in the basal ganglia are connected to areas of prefrontal cerebral cortex involved in higher cognitive functions, and these connections occur primarily via the thalamus. In patients with bipolar disorder, regardless of age, neuroimaging studies have consistently reported an increased number of white matter hyperintensities, indicating possible alterations in striatum-thalamus and thalamus-prefrontal cortex connections. METHODS: In the current study, we acquired high-resolution magnetic resonance imaging (MRI) and diffusion tensor (DT) scans of 40 patients with bipolar spectrum (BPS) illnesses (bipolar type I = 17, bipolar type II = 7, cyclothymia = 16) and 36 sex- and age-matched control subjects. Two researchers, without knowledge of diagnosis, outlined the caudate, putamen, and thalamus on contiguous axial MRI slices. We measured the volumes of the basal ganglia, thalamus, and gray/white matter of the frontal cortex. RESULTS: Bipolar spectrum patients as a single group did not differ from control subjects in thalamus and the basal ganglia volumes, but the cyclothymia patients had reductions in the volumes of putamen and the thalamus compared with control subjects. The BPS patients had significantly reduced volume of the white and the gray matter of the frontal cortex. Furthermore, compared with control subjects, BPS patients as a group showed alterations in anisotropy of the internal capsule adjacent to the striatum and thalamus and the frontal white matter. CONCLUSIONS: Our findings indicate that BPS patients may have distinct anatomical alterations in brain structures involved in the regulation of mood and cognition, as well as alterations in these structures' connection to related brain areas.

Adult↗
PubMed2005

Epsilon-sarcoglycan immunoreactivity and mRNA expression in mouse brain.

Myoclonus dystonia (M-D) is a hereditary movement disorder caused by a maternally imprinted gene that is often associated with psychiatric symptoms. Most cases of M-D are believed to result from mutations of the epsilon-sarcoglycan protein. The neuroanatomical distribution of epsilon-sarcoglycan-like immunoreactivity in mouse was investigated by using an antiserum against the epsilon-sarcoglycan protein. The expression of epsilon-sarcoglycan mRNA was studied by a sensitive fluorescence in situ hybridization (FISH) method. Immunohistochemistry and FISH revealed a wide distribution of epsilon-sarcoglycan protein and mRNA throughout the mouse brain. High expression levels of epsilon-sarcoglycan mRNA and immunoreactivity were found in the mitral cell layer of the olfactory bulb, the Purkinje cell layer in cerebellum, and the monoaminergic neurons in the mouse midbrain. Immunohistochemistry revealed a similar distribution of epsilon-sarcoglycan protein. Double-labeling FISH showed colocalization of tyrosine hydroxylase and epsilon-sarcoglycan mRNAs within all the midbrain dopaminergic (DAergic) cell groups. By combining FISH with fluorescence immunohistochemistry, coexpression of epsilon-sarcoglycan mRNA and tryptophan hydroxylase immunoreactivity was found in the serotonergic (5-HTergic) neurons within the dorsal raphe nucleus. The distribution of epsilon-sarcoglycan in the mouse brain suggests that the symptom complex of M-D may be related to the effects of decreased epsilon-sarcoglycan activity on the development or function of monoaminergic neurons.

Animals↗
PubMed2005

Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease.

This study was designed to explore the possibility that caloric restriction (CR) may benefit Alzheimer's disease (AD) by preventing beta-amyloid (Abeta) neuropathology pivotal to the initiation and progression of the disease. We report that a CR dietary regimen prevents Abeta peptides generation and neuritic plaque deposition in the brain of a mouse model of AD neuropathology through mechanisms associated with promotion of anti-amyloidogenic alpha-secretase activity. Study findings support existing epidemiological evidence indicating that caloric intake may influence risk for AD and raises the possibility that CR may be used in preventative measures aimed at delaying the onset of AD amyloid neuropathology.

Adipose Tissue↗
PubMed2005

Morphomolecular neuronal phenotypes in the neocortex reflect phylogenetic relationships among certain mammalian orders.

The cytoarchitecture of the cerebral cortex in mammals has been traditionally investigated using Nissl, Golgi, or myelin stains and there are few comparative studies on the relationships between neuronal morphology and neurochemical specialization. Most available studies on neuronal subtypes identified by their molecular and morphologic characteristics have been performed in species commonly used in laboratory research such as the rat, mouse, cat, and macaque monkey, as well as in autopsic human brain specimens. A number of cellular markers, such as neurotransmitters, structural proteins, and calcium-buffering proteins, display a highly specific distribution in distinct classes of neocortical neurons in a large number of mammalian species. In this article, we present an overview of the morphologic characteristics and distribution of three calcium-binding proteins, parvalbumin, calbindin, and calretinin, and of a component of the neuronal cytoskeleton, nonphosphorylated neurofilament protein in the neocortex of various species, representative of the major subdivisions of mammals. The distribution of these neurochemical markers defined several species- and order-specific patterns that permit assessment of the degree to which neuronal morphomolecular specialization, as well as the regional and laminar distribution of distinct cell types in the neocortex, represents derived or ancestral features. In spite of the remarkable diversity in morphologic and cellular organization that occurred during mammalian neocortical evolution, such patterns identified several associations among taxa that closely match their phylogenetic relationships.

Animals↗
PubMed2005

Brain of the African elephant (Loxodonta africana): neuroanatomy from magnetic resonance images.

We acquired magnetic resonance images of the brain of an adult African elephant, Loxodonta africana, in the axial and parasagittal planes and produced anatomically labeled images. We quantified the volume of the whole brain (3,886.7 cm3) and of the neocortical and cerebellar gray and white matter. The white matter-to-gray matter ratio in the elephant neocortex and cerebellum is in keeping with that expected for a brain of this size. The ratio of neocortical gray matter volume to corpus callosum cross-sectional area is similar in the elephant and human brains (108 and 93.7, respectively), emphasizing the difference between terrestrial mammals and cetaceans, which have a very small corpus callosum relative to the volume of neocortical gray matter (ratio of 181-287 in our sample). Finally, the elephant has an unusually large and convoluted hippocampus compared to primates and especially to cetaceans. This may be related to the extremely long social and chemical memory of elephants.

Animals↗
PubMed2005

Cortical complexity in cetacean brains.

Cetaceans (dolphins, whales, and porpoises) have a long, dramatically divergent evolutionary history compared with terrestrial mammals. Throughout their 55-60 million years of evolution, cetaceans acquired a compelling set of characteristics that include echolocation ability (in odontocetes), complex auditory and communicative capacities, and complex social organization. Moreover, although cetaceans have not shared a common ancestor with primates for over 90 million years, they possess a set of cognitive attributes that are strikingly convergent with those of many primates, including great apes and humans. In contrast, cetaceans have evolved a highly unusual combination of neurobiological features different from that of primates. As such, cetacean brains offer a critical opportunity to address questions about how complex behavior can be based on very different neuroanatomical and neurobiological evolutionary products. Cetacean brains and primate brains are arguably most meaningfully conceived as alternative evolutionary routes to neurobiological and cognitive complexity. In this article, we summarize data on brain size and hemisphere surface configuration in several cetacean species and present an overview of the cytoarchitectural complexity of the cerebral cortex of the bottlenose dolphin.

Animals↗
PubMed2005

Nature's experiments in brain diversity.

This special issue of The Anatomical Record originates from a symposium on the evolution of neurobiological specializations in mammals held at the American Association of Anatomists annual meeting in San Diego in April 2005. The symposium, co-organized by Patrick R. Hof and Lori Marino, provided the impetus for extending the discussion to a greater range of species. This special issue is the product of that goal and is fueled by the philosophy that it is largely against a backdrop of brain diversity that we can extract the higher-order commonalities across brains that may lead us to uncovering general higher-order principles of brain and behavioral evolution. Several major themes emerge from this issue. These are that there are no simple brains, that brains reflect ecology, and that brain evolution is a detective story. The 12 articles in this issue are outstanding reflections of these themes.

Animals↗
PubMed2005

Cellular and synaptic distribution of NR2A and NR2B in macaque monkey and rat hippocampus as visualized with subunit-specific monoclonal antibodies.

The functional and pharmacological attributes of the N-methyl-D-aspartate (NMDA) receptor are related to its subunit composition, thus resolving the subunit composition of NMDA receptors in specific classes of synapses is an important step in characterizing excitatory circuits. Toward this end, mouse monoclonal antibodies were raised against fusion protein antigens corresponding to the putative amino acid sequences of human NMDA receptor subunits NR2A and NR2B. The subunit specificity of these monoclonal antibodies was demonstrated with transfected human and rat NMDA receptor cDNAs, and their immunoreactivity was established in rat, macaque monkey, and human brain tissue. At the light microscopic level, both NR2A and NR2B exhibit a distribution in monkey and rat hippocampus very similar to NMDA receptor subunit NR1, and both are highly colocalized with NR1. Electron microscopic immunogold studies demonstrated that both NR2A and NR2B are often present in asymmetric synapses in CA1, commonly colocalized with NR1, and often colocalized with each other in the same asymmetric synapses. Both assembly and synthetic pools are present within spines and spine necks, respectively, particularly for NR2A. The confocal and ultrastructural data suggest that whereas NR1, NR2A, and NR2B are essentially uniformly colocalized in hippocampal projection neurons, there is extensive heterogeneity at the synaptic level that would lead to multiple functional classes of NMDA receptor-mediated synapses, and extensive capacity for plasticity at the synapse. Thus, the subunit profile of a given synapse may be dynamic, with regulation of local synthesis and insertion of different subunits into the synapse leading to a complex, heterogeneous, and shifting set of functional attributes of the NMDA receptor.

Animals↗
PubMed2005

Stereologic analysis of hippocampal Alzheimer's disease pathology in the oldest-old: evidence for sparing of the entorhinal cortex and CA1 field.

Several neuropathologic analyses postulate that Alzheimer disease (AD) in the oldest-old is associated with substantial neurofibrillary tangle (NFT) formation in the CA fields of the hippocampus and neuronal loss confined to the entorhinal cortex. All of these studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathological hallmarks in a global multivariate analysis. We present here a stereologic analysis of AD-related pathology in 12 oldest-old individuals including a complete assessment of total NFT, neuron numbers and amyloid volume in entorhinal cortex, CA fields, and dentate gyrus. The progression of NFT numbers and amyloid volume across the different Clinical Dementia Rating (CDR) groups was significantly slower in these cases compared to previously reported younger cases. Although patients with mild and moderate dementia showed significantly lower mean neuron numbers compared to CDR 0-0.5 cases, there was a marked overlap in individual values among CDR groups. A modest proportion of the variability in CDR scores was explained by NFT numbers in the CA2 field (18.1%) and the dentate gyrus (17.3%). In contrast, neither Nissl-stained neuron numbers nor total amyloid volume in the areas studied significantly predicted cognitive status. These data indicate that the occurrence and progression of AD-related pathologic changes are not an unavoidable consequence of aging. They also suggest that dementia in extreme aging depends more on the damage of hippocampal subdivisions commonly less affected than on severe NFT formation and neuronal loss in the CA1 field and entorhinal cortex.

Aged↗