Jonathan Nissanov

Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease.

Abnormally phosphorylated tau accumulates as neurofibrillary tangles and neuropil threads in older persons with and without Alzheimers disease. The relationship between neurofibrillary tangles and neuropil threads and how they relate to cognitive function is unknown. This study investigated the relationship between phosphorylated tau lesions and cognitive function in 31 persons participating in the Religious Orders Study, a prospective, longitudinal clinicopathological study of aging and Alzheimers disease. All subjects underwent detailed neuropsychological performance testing within a year of death and evidenced a spectrum of cognitive performance ranging from normal abilities to mild dementia. Measures of neurofibrillary tangle density and phosphorylated tau immunoreactive structures (predominantly neuropil threads) in the entorhinal and perirhinal cortices by quantitative image analysis were significantly correlated (r = 0.5). In multiple linear regression analyses controlling for age, sex, and education, parahippocampal neurofibrillary tangles and neuropil threads were significantly lower in persons without cognitive impairment compared to those with mild cognitive impairment and/or Alzheimers disease. Further, neurofibrillary tangles were significantly correlated to measures of episodic memory but not other cognitive abilities; neuropil tangles were not significantly related to memory or other cognitive functions. These data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory.

Role of the Mauthner Cell in Sensorimotor Integration by the Brain Stem Escape Network

The Mauthner neurons have become synonymous with the C start evasive response of fishes. C starts are a two-part movement pattern. First, the fish bends its body so that it has a C-like profile (stage 1) when viewed from above. Second, the fish rapidly accelerates away from its starting position (stage 2). Until recently, it has been possible to determine the contribution of Mauthner cell activity to the expression of this behavior. In this paper we focus on three of our recent papers that address this issue. Our work combines high-speed digital image analysis of the C start with chronic Mauthner cell and electromyographic recordings, lesions of the Mauthner cells, and stimulation of single Mauthner axons in swimming fishes. This work shows that the firing of the Mauthner cell results in a short-latency body contraction that orients the initial stage of the C start away from the direction of the threatening stimulus. The direction of the escape trajectory, however, is more finely tuned to stimulus angle than can be explained by the firing of just the Mauthner cell and its post-synaptic followers. Precise control of trajectory must, therefore, require participation of other neurons. These neurons together with the Mauthner cell form a system that we term the brain stem escape network. We have identified candidate neurons of this network which can now be studied at the single-cell level. Because of both its accessibility for neurophysiological study and its neuroanatomical simplicity, we assert that the brain stem escape network is a useful preparation for understanding fundamental processes of sensorimotor integration in the brain stem.

Waxholm Space: An image-based reference for coordinating mouse brain research

We describe an atlas of the C57BL/6 mouse brain based on MRI and conventional Nissl histology. Magnetic resonance microscopy was performed on a total of 14 specimens that were actively stained to enhance tissue contrast. Images were acquired with three different MR protocols yielding contrast dependent on spin lattice relaxation (T1), spin spin relaxation (T2), and magnetic susceptibility (T2*). Spatial resolution was 21.5 mum (isotropic). Conventional histology (Nissl) was performed on a limited set of these same specimens and the Nissl images were registered (3D-to-3D) to the MR data. Probabilistic atlases for 37 structures are provided, along with average atlases. The availability of three different MR protocols, the Nissl data, and the labels provides a rich set of options for registration of other atlases to the same coordinate system, thus facilitating data-sharing. All the data is available for download via the web.

MRI diffusion coefficients in spinal cord correlate with axon morphometry.

Following spinal cord injury, diffusion MRI (DWI) has been shown to detect injury and functionally significant neuroprotection following treatment that otherwise would go undetected with conventional MRI. The underlying histologic correlates to directional apparent diffusion coefficients (ADC) obtained with DWI have not been determined, however, and we address this issue by directly correlating ADC values with corresponding axon morphometry in the normal rat cervical spinal cord. ADC values transverse (perpendicular) and longitudinal (parallel) to axons both correlate with axon counts, however each directional ADC reflects distinct histologic parameters. DWI may therefore be capable of providing specific histologic data regarding the integrity of white matter.

Differential activation of Mauthner and non-Mauthner startle circuits in the zebrafish: Implications for functional substitution

Summary1.The Mauthner (M-) cell triggers a complex startle or escape movement when the zebrafish,Brachydanio rerio, is presented with a sudden vibrational stimulus. Alternative (non-Mauthner) circuits functionally substitute for the M-cell to produce similar behavior patterns when the M-cell is missing or fails to fire. These responses are called non-Mauthner responses. In this paper, we demonstrate that vibrational stimulation of the tail reliably elicits responses initiated by non-Mauthner circuits in animals with intact M-cells. We conclude that such non-Mauthner circuits can functionally substitute for the M-cell in generating the escape response.2.To characterize sensory pathways responsible for activating the Mauthner and non-Mauthner responses in intact animals, we made detailed comparisons of response thresholds and latencies to vibrational stimuli applied to the head and the tail.3.In a comparison of vibrational stimulation applied to the head versus the tail, the M-cell was more sensitive to vibrational stimuli applied to the head. In pairwise comparisons the M-cell had the lowest threshold to the head stimulus in about 62% of the trials and the shortest latency in 79% of the trials (Table 1). For responses initiated by non-Mauthner cells, there was no difference in threshold to head and tail stimuli, but shorter latencies occurred when the head was stimulated than when the tail was stimulated (Table 1).4.In a comparison of Mauthner and non-Mauthner responses, we found that in 77% of the trials, Mauthner responses occurred at lower stimulus intensities than the responses initiated by non-Mauthner circuits when a vibrational stimulus was applied to the head. But, when the tail was stimulated, there was no apparent difference in stimulus intensity required to elicit Mauthner responses and responses initiated by non-Mauthner circuits. The Mauthner responses were always substantially shorter in latency (by an average of 15 or 21 ms) than the responses initiated by non-Mauthner circuits when stimulating either the head or tail.5.We conclude that at least two sensory systems are involved in the activation of these startle systems when stimulating the head and tail of the zebrafish. One system is the otolithic receptors of the ear and another is probably either the posterior lateral line or Rohon-Beard cell system. The findings are discussed in terms of a general model that provides a mechanism for functional substitution of responses initiated by non-Mauthner circuits for Mauthner responses.

The motor output of the Mauthner cell, a reticulospinal command neuron.

We electrically stimulated individual Mauthner (M-) cells to determine their motor contribution to C-starts of swimming goldfish. In comparison with sensory-evoked C-starts, M-reflexes triggered by electrical stimulation of single M-cells were significantly weaker and less variable. Stage 1 turns were both longer in duration and smaller in angle for the M-reflex when compared with the sensory-evoked C-start. This translates to an average reduction of 22% in angular velocity during stage 1. Likewise, during stage 2, the distance moved by the fish was reduced by 15% and the absolute value of stage 2 turning angle was reduced by 47%. In addition, the normal mechanical or neural coupling between stages 1 and 2 appeared to be altered for the M-reflex. From this and our other recent studies, we conclude that there must be two primary groups of reticulospinal neurons in the escape triggering network. The first group includes the M-cell and determines the initial left-right direction of the response and the extent of stage 1 angle. From previous EMG recordings we know that the second group of neurons can fire within 5-15 ms (average, 9 ms) after the stage 1 cells. These determine the onset time and direction of stage 2. Together the coupling of the two primary groups results in the full propulsive force and turning flexibility of the C-start.

Multidimensional alignment using the Euclidean distance transform

Abstract We present a methodology for alignment of multidimensional data sets that is based on the Euclidean distance transform and the Marquardt–Levenberg optimization algorithm. The proposed approach operates on pixel or voxel descriptions of objects to be matched and estimates the parameters of a space transformation for optimal alignment of objects. The computational cost of an algorithm developed with this method is estimated. The methodology is tested by developing an algorithm for rigid body transformation alignment of three-dimensional data sets. Tests with synthetic and real objects indicate that the method is accurate, reliable, and robust.

Novel Method to Quantify Neuropil Threads in Brains from Elders With or Without Cognitive Impairment

Pathological alterations in dendrites and axons (i.e., neuritic pathologies) occur in the normal aging brain as well as in brains from elders with mild cognitive impairment and neurodegenerative dementia. These alterations may correlate with clinical measures of cognitive abilities, but the contribution of neuropil threads (NTs), which constitute 85–90% of cortical tau pathology, has not been clear because of the lack of quantitative methodologies. We combined quantitative fractionation and image analysis to devise a strategy for measuring the burden of tau-rich NTs in the entorhinal and perirhinal cortex of brains from elders with and without cognitive impairment, including dementia due to Alzheimers disease (AD). On the basis of data presented here using this novel strategy, we conclude that this quantitative imaging technique will facilitate efforts to determine the behavioral correlations of neuritic lesions in AD and other brain disorders.

Thyroid hormone distribution in the mouse brain: the role of transthyretin

Transthyretin is the major thyroxine-binding protein in the plasma of rodents, and the main thyroxine-binding protein in the cerebrospinal fluid of both rodents and humans. The choroid plexus synthesizes transthyretin and secretes it to the cerebrospinal fluid. Although it was suggested that transthyretin might play an important role in mediating thyroxine transfer from the blood into the brain across the choroid plexus-cerebrospinal fluid barrier, newer findings question this hypothesis. Because thyroid hormone passage across brain barriers is a precondition for its action in the CNS, and because brain is an important target of thyroid hormone action, we investigated the role of transthyretin in mediating thyroid hormone access to and distribution within the brain in a transthyretin-null mouse model system. In this report we describe the results derived from use of film autoradiography, a technique that yields definitive morphological results. Film autoradiograms were prepared at 3 and 19 h after intravenous injection of either high specific activity [(125)I]thyroxine or [(125)I]triiodothyronine. Image analyses were designed to demonstrate regional changes in hormone distribution, and to highlight alterations in iodothyronine delivery from ventricles to brain parenchyma. We find no qualitative or quantitative differences in these parameters between the transthyretin-null and the wild-type mouse brain after either [(125)I]thyroxine or [(125)I]triiodothyronine administration. The data presented here now provide definitive evidence that, under standard laboratory conditions, transthyretin is not required for thyroid hormone access to or distribution within the mouse brain. This study also provides the first map of iodothyronine distribution in the brain of the mouse.

Lateralization and adaptation of a continuously variable behavior following lesions of a reticulospinal command neuron

This study utilizes digitized cinematic data and lesions of individual Mauthner (M-) cells, large medial reticulospinal command neurons, to examine their role in goldfish C-starts elicited by displacement stimuli. Our results show a major difference in response lateralization in animals with only one M-cell compared to those with both cells intact, or both cells absent. Animals with one M-cell responded by turning to the side opposite the remaining M-cell in 94% of the trials, whereas those with both M-cells intact or both cells absent responded with equal probability to both sides. When the M-cells were absent, the responses were on the average 4 ms longer in latency. This difference may confer a behaviorally significant advantage to the M-cell in blocking other networks that can trigger C-starts. Nevertheless, with the exception of latency, the central program producing the escape behavior adapts automatically to the absence of both M-cells: animals with bilateral M-cell lesions continued to produce the full spectrum of kinematic performance levels seen in intact animals.