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1.  Potential utility of aquaporin modulators for therapy of brain disorders 
Progress in brain research  2008;170:589-601.
Of the several aquaporin (AQP) water channels expressed in the central nervous system, AQP4 is an attractive target for drug discovery. AQP4 is expressed in astroglia, most strongly at the blood–brain and brain–cerebrospinal fluid barriers. Phenotype analysis of AQP4 knockout mice indicates the involvement of AQP4 in three distinct processes: brain water balance, astroglial cell migration and neural signal transduction. By slowing water uptake into the brain, AQP4 knockout mice manifest reduced brain swelling and improved outcome in models of cytotoxic cerebral oedema such as water intoxication, focal ischaemia and meningitis. However, by slowing the clearance of excess water from brain, AQP4 knockout mice do worse in models of vasogenic oedema such as brain tumour, abscess and hydrocephalus. AQP4 deficient astroglial cells show greatly impaired migration in response to chemotactic stimuli, reducing glial scar formation, by a mechanism that we propose involves AQP4-facilitated water flux in lamellipodia of migrating cells. AQP4 knockout mice also manifest increased seizure threshold and duration, by a mechanism that may involve slowed K+ uptake from the extracellular space (ECS) following neuroexcitation, as well as ECS expansion. Notwithstanding challenges in drug delivery to the central nervous system and their multiplicity of actions, AQP4 inhibitors have potential utility in reducing cytotoxic brain swelling, increasing seizure threshold and reducing glial scar formation; enhancers of AQP4 expression have potential utility in reducing vasogenic brain swelling. AQP4 modulators may thus offer new therapeutic options for stroke, tumour, infection, hydrocephalus, epilepsy and traumatic brain and spinal cord injury.
doi:10.1016/S0079-6123(08)00446-9
PMCID: PMC3601944  PMID: 18655912
AQP4; water transport; transgenic mouse; brain oedema; cell migration; epilepsy
2.  Endogenous modulators of synaptic transmission: cannabinoid regulation in the supraoptic nucleus 
Progress in brain research  2008;170:129-136.
The magnocellular neurons of the hypothalamic supraoptic nucleus (SON) are a major source of both systemic and central release of the neurohypophyseal peptides, oxytocin (OXT) and arginine–vasopressin (AVP). Both OXT and AVP are released from the somatodendritic compartment of magnocellular neurons and act within the SON to modulate the electrophysiological function of these cells. Cannabinoids (CBs) affect hormonal output and the SON may represent a neural substrate through which CBs exert specific physiological and behavioural effects. Dynamic modulation of synaptic inputs is a fundamental mechanism through which neuronal output is controlled. Dendritically released OXT acts on autoreceptors to generate endocannabinoids (eCBs) which modify both excitatory and inhibitory inputs to OXT neurons through actions on presynaptic CB receptors. As such, OXT and eCBs cooperate to shape the electrophysiological properties of magnocellular OXT neurons, regulating the physiological function of this nucleus. Further study of eCB signalling in the SON, including its interaction with AVP neurons, promises to extend our understanding of the synaptic regulation of SON physiological function.
doi:10.1016/S0079-6123(08)00412-3
PMCID: PMC3569497  PMID: 18655878 CAMSID: cams2631
hypothalamus; oxytocin; magnocellular neurons; retrograde messengers
3.  Structural and functional plasticity of the human brain in posttraumatic stress disorder 
Progress in brain research  2008;167:171-186.
Posttraumatic stress disorder (PTSD) is associated with long-term changes in neurobiology. Brain areas involved in the stress response include the medial prefrontal cortex, hippocampus, and amygdala. Neurohormonal systems that act on the brain areas to modulate PTSD symptoms and memory include glucocorticoids and norepinephrine. Dysfunction of these brain areas is responsible for the symptoms of PTSD. Brain imaging studies show that PTSD patients have increased amygdala reactivity during fear acquisition. Other studies show smaller hippocampal volume. A failure of medial prefrontal/anterior cingulate activation with re-experiencing of the trauma is hypothesized to represent a neural correlate of the failure of extinction seen in PTSD. The brain has the capacity for plasticity in the aftermath of traumatic stress. Antidepressant treatments and changes in environment can reverse the effects of stress on hippocampal neurogenesis, and humans with PTSD showed increased hippocampal volume with both paroxetine and phenytoin.
doi:10.1016/S0079-6123(07)67012-5
PMCID: PMC3226705  PMID: 18037014
PET; depression; cortisol; glucocorticoids; stress; PTSD
4.  TNF-α Signaling in Glaucomatous Neurodegeneration 
Progress in brain research  2008;173:409-421.
Growing evidence supports the role of TNF-α as a mediator of neurodegeneration in glaucoma. Glial production of TNF-α is increased and its death receptor is up-regulated on retinal ganglion cells (RGCs) and optic nerve axons in glaucomatous eyes. This multifunctional cytokine can induce RGC death through receptor-mediated caspase activation, mitochondrial dysfunction, and oxidative stress. Opposing these cell-death promoting signals, binding of TNF receptors can also trigger the activation of survival signals. A critical balance between a variety of intracellular signaling pathways determines the predominant in vivo bioactivity of TNF-α as best exemplified by differential responses of RGCs and glia. In addition to the direct neurotoxicity of TNF-α to RGCs and their axons, potential interplay of TNF-α signaling with other cellular events associated with glaucomatous neurodegeneration may also contribute to secondary neurodegenerative injury. This review focuses on the present evidence supporting the involvement of TNF-α signaling in glaucomatous neurodegeneration and possible treatment targets to provide neuroprotection.
doi:10.1016/S0079-6123(08)01128-X
PMCID: PMC3150483  PMID: 18929124
glaucoma; neurodegeneration; retinal ganglion cell; glia; tumor necrosis factor-alpha
5.  Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase 
Progress in brain research  2008;169:97-115.
The hippocampus is crucial for the consolidation of new declarative long-term memories. Genetic and behavioral experimentation have revealed that several protein kinases are critical for the formation of hippocampus-dependent long-term memories. Cyclic-AMP dependent protein kinase (PKA) is a serine–threonine kinase that has been strongly implicated in the expression of specific forms of hippocampus-dependent memory. We review evidence that PKA is required for hippocampus-dependent memory in mammals, and we highlight some of the proteins that have been implicated as targets of PKA. Future directions and open questions regarding the role of PKA in memory storage are also described.
doi:10.1016/S0079-6123(07)00006-4
PMCID: PMC2914307  PMID: 18394470
memory; learning; cyclic AMP-dependent protein kinase; hippocampus; synaptic plasticity; long-term potentiation
6.  Functional Anatomy of the Extraocular Muscles During Vergence 
Progress in brain research  2008;171:21-28.
Magnetic resonance imaging (MRI) now enables precise visualization of the mechanical state of the living human orbit, enabling inferences about the effects of mechanical factors on ocular kinematics. We used 3-dimensional magnetic search coil recordings and MRI to investigate the mechanical state of the orbit during vergence in humans. Horizontal convergence of 23° from a remote to a near target aligned on one eye was geometrically ideal, and was associated with lens thickening and extorsion of the rectus pulley array of the aligned eye with superior oblique muscle relaxation and inferior oblique muscle contraction. There was no rectus muscle cocontraction. Subjective fusion through a 1° vertical prism caused a clockwise (CW) torsion in both eyes, as well as variable vertical and horizontal vergences that seldom corresponded to prism amount or direction. MRI under these conditions did not show consistent torsion of the rectus pulley array, but a complex pattern of changes in rectus extraocular muscle (EOM) crossections, consistent with co-contraction. Binocular fusion during vergence is accomplished by complex, 3D eye rotations seldom achieving binocular retinal correspondence. Vergence eye movements are sometimes associated with changes in rectus EOM pulling directions, and may sometimes be associated with co-contraction. Thus, extraretinal information about eye position would appear necessary to interpret binocular correspondence, and to avoid diplopia.
doi:10.1016/S0079-6123(08)00604-3
PMCID: PMC2881303  PMID: 18718278
active pulley hypothesis; extraocular muscles; magnetic resonance imaging; pulleys; vergence
7.  Defining the Pupillary Component of the Perioculomotor Preganglionic Population within a Unitary Primate Edinger-Westphal Nucleus 
Progress in brain research  2008;171:97-106.
The primate Edinger-Westphal nucleus (EW) contains perioculomotor preganglionic (pIIIPG) motoneurons that control the lens and pupil. Separate subdivisions have been described in EW and termed visceral columns, with the lateral visceral column (lvc) reportedly receiving pretectal inputs for the pupillary light reflex. However, choline acetyl transferase staining reveals a single paired column of cells dorsal to the oculomotor nucleus, suggesting the EW is not subdivided. We investigated this issue by transneuronal retrograde labeling of pIIIPG neurons in three monkey species. In all three, pIIIPG neurons were contained in a single column. We have also examined which part of the macaque pIIIPG population receives pretectal input. Injections of biocytin into the pretectum anterogradely labeled terminals that lay in close association with pIIIPG motoneurons retrogradely labeled by ciliary ganglion injections of WGA-HRP. These close associations were concentrated in the ventromedial portion of the middle third of EW, suggesting this pIIIPG region mediates pupillary control. In other cases, pretectal WGA-HRP injections, in addition to labeling terminals in the EW, produced a circular field of labeled neurons and terminals in the periaqueductal gray, dorsolateral to EW. This region may represent the previously designated lvc, but it does not contain pIIIPG motoneurons.
doi:10.1016/S0079-6123(08)00613-4
PMCID: PMC2859175  PMID: 18718287
8.  New Tricks for an Old Slug: The Critical Role of Postsynaptic Mechanisms in Learning and Memory in Aplysia 
Progress in brain research  2008;169:277-292.
The marine snail Aplysia has served for more than four decades as an important model system for neurobiological analyses of learning and memory. Until recently, it has been believed that learning and memory in Aplysia were due predominately, if not exclusively, to presynaptic mechanisms. For example, two nonassociative forms of learning exhibited by Aplysia, sensitization and dishabituation of its defensive withdrawal reflex, have been previously ascribed to presynaptic facilitation of the connections between sensory and motor neurons that mediate the reflex. Recent evidence, however, indicates that postsynaptic mechanisms play a far more important role in learning and memory in Aplysia than formerly appreciated. In particular, dishabituation and sensitization depend on a rise in intracellular Ca2+ in the postsynaptic motor neuron, postsynaptic exocytosis, and modulation of the functional expression of postsynaptic AMPA-type glutamate receptors. In addition, the expression of the persistent presynaptic changes that occur during intermediate- and long-term dishabituation and sensitization appears to require retrograde signals that are triggered by elevated postsynaptic Ca2+. The model for learning-related synaptic plasticity proposed here for Aplysia is similar to current mammalian models. This similarity suggests that the cellular mechanisms of learning and memory have been highly conserved during evolution.
doi:10.1016/S0079-6123(07)00017-9
PMCID: PMC2855241  PMID: 18394481
9.  EXPLORING THE PULVINAR PATH TO VISUAL CORTEX 
Progress in brain research  2008;171:467-473.
The primary pathway for visual signals from the retina to cerebral cortex is through the lateral geniculate nucleus of the thalamus to primary visual cortex. A second visual pathway has been postulated to pass through the thalamic pulvinar nucleus and to project to multiple regions of visual cortex. We have explored this second visual pathway using a method that allows us to identify the inputs and outputs of pulvinar neurons. Specifically, we applied microstimulation in the superficial layers of superior colliculus (SC) to test for orthodromic activation of pulvinar neurons receiving input from SC. We also microstimulated the cortical motion area MT and tested for antidromic activation of pulvinar to identify neurons projecting to MT (and to determine the presence of orthodromic input back to pulvinar). In this initial report, we concentrate on two observations. First, we find that there are clusters of neurons in the pulvinar that receive input from SC along with neurons that project to MT or receive input from MT. Second, we find that neurons with input from SC have characteristics of the SC superficial layers: they respond to visual stimuli but do not discharge before saccadic eye movements. Neurons projecting to MT respond similarly to these SC-input neurons, while those receiving input from MT more frequently show directional selectivity as does MT. These findings indicate the visual nature of the signals conveyed in this pathway and shed light on the functional role of the thalamus in a possible second visual pathway.
doi:10.1016/S0079-6123(08)00668-7
PMCID: PMC2802535  PMID: 18718342
Pulvinar; Superior Colliculus; MT; Two Visual Pathways; Monkey Visual Pathways
10.  Ocular motor anatomy in a case of interrupted saccades 
Progress in brain research  2008;171:563-566.
Saccades normally place the eye on target with one smooth movement. In late-onset Tay—Sachs (LOTS), intrasaccadic transient decelerations occur that may result from (1) premature omnipause neuron (OPN) re-activation due to malfunction of the latch circuit that inhibits OPNs for the duration of the saccade or (2) premature inhibitory burst neuron (IBN) activation due to fastigial nucleus (FN) dysregulation by the dorsal cerebellar vermis. Neuroanatomic analysis of a LOTS brain was performed. Purkinje cells were absent and gliosis of the granular cell layer was present in the dorsal cerebellar vermis. Deep cerebellar nuclei contained large inclusions. IBNs were present with small inclusions. The sample did not contain the complete OPN region; however, neurons in the OPN region contained massive inclusions. Pathologic findings suggest that premature OPN re-activation and/or inappropriate firing of IBNs may be responsible for interrupted saccades in LOTS. Cerebellar clinical dysfunction, lack of saccadic slowing, and significant loss of cerebellar cells suggest that the second cause is more likely.
doi:10.1016/S0079-6123(08)00680-8
PMCID: PMC2752380  PMID: 18718354
fastigial nucleus; omnipause neurons; burst neurons; latch circuit; brainstem
11.  Mechanism of interrupted saccades in patients with late-onset Tay-Sachs disease 
Progress in brain research  2008;171:567-570.
In late-onset Tay-Sachs disease (LOTS), saccades are interrupted by one or more transient decelerations. Some saccades reaccelerate and continue on before eye velocity reaches zero, even in darkness. Intervals between successive decelerations are not regularly spaced. Peak decelerations of horizontal and vertical components of oblique saccades in LOTS is more synchronous than those in control subjects. We hypothesize that these decelerations are caused by dysregulation of the fastigial nuclei (FN) of the cerebellum, which fire brain stem inhibitory burst neurons (IBNs).
doi:10.1016/S0079-6123(08)00681-X
PMCID: PMC2750844  PMID: 18718355
fastigial nucleus; omnipause neurons; burst neurons; latch circuit
12.  The role of omnipause neurons 
Progress in brain research  2008;171:115-121.
The anatomy and neurophysiology of the saccadic eye movement system have been well studied, but the roles of certain key neurons in this system are not fully appreciated. Important clues about the functional interactions in the saccadic system can be gleaned from the histochemistry of different saccadic neurons. The most prominent inhibitory neurons in the circuit are the omnidirectional pause neurons (OPN), which inhibit the premotor burst neurons that drive the eye. Most inhibitory neurons in the brain transmit γ-aminobutyric acid (GABA), but OPN transmit glycine (Gly). It is interesting to ask whether the saccadic system would work any differently if OPN were GABA-ergic. Gly and GABA receptors both provide a channel for a hyperpolarizing Cl- current that inhibits its target neuron. Depolarizing currents that excite the neurons come through several channels, including the NMDA receptor (NMDAR). The NMDAR is unique among receptors in that it has active sites for two different neurotransmitters, glutamate (Glu) and Gly. Gly is a co-agonist that acts to amplify the current produced by Glu. We have proposed a model of the saccadic brain stem circuitry that exploits this dual role of Gly to produce both inhibition of the saccadic circuit during fixation, and to increase its responsiveness, or gain, during movements. This suggests that OPNs act more as a regulator of the saccadic circuit’s gain, rather than as a gate for allowing saccades. We propose a new hypothesis: the OPNs play a general role as a modulator of arousal in orienting subsystems, such as saccades, pursuit, head movements, etc.
doi:10.1016/S0079-6123(08)00615-8
PMCID: PMC2750832  PMID: 18718289
glycine; burst neurons; brainstem; saccades
13.  Brain mechanisms for switching from automatic to controlled eye movements 
Progress in brain research  2008;171:375-382.
Human behaviour is mostly composed of habitual actions that require little conscious control. Such actions may become invalid if the environment changes, at which point we need to switch behaviour by overcoming habitual actions that are otherwise triggered automatically. It is unclear how the brain controls this type of behavioural switching. Here we show that the presupplementary motor area (pre-SMA) in the medial frontal cortex has a function in switching from automatic to volitionally controlled action. This was demonstrated using colour-matching saccade tasks performed by rhesus monkeys. We found that a group of pre-SMA neurons was selectively activated when subjects successfully switched from a habitual saccade to a controlled alternative saccade. Electrical stimulation in the pre-SMA replaced automatic incorrect saccades with slower correct saccades. A further test suggested that the pre-SMA enabled switching by first suppressing an automatic unwanted saccade and then boosting a controlled desired saccade. Our data suggest that the pre-SMA resolves response conflict so that the desired action can be selected. Possible neuronal circuits through which the pre-SMA might exert its switching functions will be discussed.
doi:10.1016/S0079-6123(08)00655-9
PMCID: PMC2747307  PMID: 18718329
presupplementary motor area; medial frontal cortex; subthalamic nucleus; substantia nigra pars reticulata; basal ganglia; monkeys; saccadic eye movement; habitual action; conscious control; decision-making
14.  Negative motivational control of saccadic eye movement by the lateral habenula 
Progress in brain research  2008;171:399-402.
Reward is crucial for survival of animals and influences animal behaviors. For example, an approaching behavior to reward is more frequently and quickly elicited when big reward is expected than when small reward is expected. Midbrain dopamine neurons are thought to be crucial for such reward-based control of motor behavior. Indeed, dopamine neurons are excited by cues predicting reward and inhibited by cues predicting no-reward. These excitatory and inhibitory signals would then be used for enhancing and depressing sensorimotor processing, respectively, in the brain areas targeted by dopamine neurons (e.g., striatum). However, it was unknown which parts of the brain provide dopamine neurons with reward-related signals necessary for their responses. We recently showed evidence that the lateral habenula transmits reward-related signals to dopamine neurons, especially to inhibit dopamine neurons. This recent study suggested that the lateral habenula suppresses less rewarding saccadic eye movements by inhibiting dopamine neurons. In the present review, we first summarize anatomical and functional aspects of the lateral habenula. We will then describe our own study. Finally, we will discuss how the lateral habenula, as well as dopamine neurons, contributes to the reward-based control of saccadic eye movements.
doi:10.1016/S0079-6123(08)00658-4
PMCID: PMC2735791  PMID: 18718332
reward; lateral habenula; dopamine neuron; saccade; monkey
15.  Lesions of the Cerebellar Nodulus and Uvula in Monkeys: Effect on Otolith-Ocular Reflexes 
Progress in brain research  2008;171:167-172.
We studied two rhesus monkeys before and after surgical ablation of the nodulus and uvula (Nod/Uv) of the cerebellum. Three-axis eye movements were recorded with the magnetic-field scleral search coil system during a variety of vestibular and ocular motor tasks. Here we describe the effects of the Nod/Uv lesions on dynamic (head translation) and static (head tilt) otolith-mediated vestibulo-ocular reflexes. The main findings were: 1) eye velocity during sinusoidal vertical translation (1.5 Hz) was reduced by 59% in the dark and 36% in the light; 2) eye velocity during steps of horizontal translation was reduced, but only in the dark and more so during the sustained (constant-velocity) than the initial (acceleration) part of the response, and 3) there was a torsional nystagmus that depended on the position of roll head tilt, but static ocular counterroll was unchanged. These results suggest new roles for the Nod/Uv in the processing of otolith signals. This is likely important not only for facilitating gaze during linear head motion, but also for maintaining postural stability and one’s orientation relative to gravity. The lesions appeared to have a greater effect on responses to vertical motion, particularly in the light (in contrast responses to interaural translation in the light were nearly normal), suggesting a particular importance of the Nod/Uv in processing signals arising from the sacculi.
doi:10.1016/S0079-6123(08)00622-5
PMCID: PMC2718056  PMID: 18718296
16.  Olfactory memory traces in Drosophila 
Progress in brain research  2008;169:293-304.
In Drosophila the fruit fly, coincident exposure to an odor and an aversive electric shock can produce robust behavioral memory. This behavioral memory is thought to be regulated by cellular memory traces within the central nervous system of the fly. These molecular, physiological or structural changes in neurons, induced by pairing odor and shock, regulate behavior by altering the neurons’ response to the learned environment. Recently, novel in vivo functional imaging techniques have allowed researchers to observe cellular memory traces in intact animals. These investigations have revealed interesting temporal and spatial dynamics of cellular memory traces. First, a short-term cellular memory trace was discovered that exists in the antennal lobe, an early site of olfactory processing. This trace represents the recruitment of new synaptic activity into the odor representation and forms for only a short period of time just after training. Second, an intermediate-term cellular memory trace was found in the dorsal paired medial neuron, a neuron thought to play a role in stabilizing olfactory memories. Finally, a long-term protein synthesis-dependent cellular memory trace was discovered in the mushroom bodies, a structure long implicated in olfactory learning and memory. Therefore, it appears that aversive olfactory associations are encoded by multiple cellular memory traces that occur in different regions of the brain with different temporal domains.
doi:10.1016/S0079-6123(07)00018-0
PMCID: PMC2692900  PMID: 18394482
Drosophila; mushroom body; olfactory learning; memory trace
17.  Differential mechanisms of transmission and plasticity at mossy fiber synapses 
Progress in brain research  2008;169:225-240.
The last few decades have seen the hippocampal formation at front and center in the field of synaptic transmission. However, much of what we know about hippocampal short- and long-term plasticity has been obtained from research at one particular synapse; the Schaffer collateral input onto principal cells of the CA1 subfield. A number of recent studies, however, have demonstrated that there is much to be learned about target-specific mechanisms of synaptic transmission by study of the lesser known synapse made between the granule cells of the dentate gyrus; the so-called mossy fiber synapse, and its targets both within the hilar region and the CA3 hippocampus proper. Indeed investigation of this synapse has provided an embarrassment of riches concerning mechanisms of transmission associated with feedforward excitatory and inhibitory control of the CA3 hippocampus. Importantly, work from a number of labs has revealed that mossy fiber synapses possess unique properties at both the level of their anatomy and physiology, and serve as an outstanding example of a synapse designed for target-specific compartmentalization of synaptic transmission. The purpose of the present review is to highlight several aspects of this synapse as they pertain to a novel mechanism of bidirectional control of synaptic plasticity at mossy fiber synapses made onto hippocampal stratum lucidum interneurons. It is not my intention to pour over all that is known regarding the mossy fiber synapse since many have explored this topic exhaustively in the past and interested readers are directed to other fine reviews (Henze et al., 2000; Urban et al., 2001; Lawrence et al., 2003; Bischofberger et al., 2006; Nicoll and Schmitz, 2005).
doi:10.1016/S0079-6123(07)00013-1
PMCID: PMC2671885  PMID: 18394477
hippocampus; local circuit inhibitory interneuron; long-term depression; glutamate receptors; plasticity; mossy fiber; mGluR7
18.  What are the differences between long-term, short-term, and working memory? 
Progress in brain research  2008;169:323-338.
In the recent literature there has been considerable confusion about the three types of memory: long-term, short-term, and working memory. This chapter strives to reduce that confusion and makes up-to-date assessments of these types of memory. Long- and short-term memory could differ in two fundamental ways, with only short-term memory demonstrating (1) temporal decay and (2) chunk capacity limits. Both properties of short-term memory are still controversial but the current literature is rather encouraging regarding the existence of both decay and capacity limits. Working memory has been conceived and defined in three different, slightly discrepant ways: as short-term memory applied to cognitive tasks, as a multi-component system that holds and manipulates information in short-term memory, and as the use of attention to manage short-term memory. Regardless of the definition, there are some measures of memory in the short term that seem routine and do not correlate well with cognitive aptitudes and other measures (those usually identified with the term “working memory”) that seem more attention demanding and do correlate well with these aptitudes. The evidence is evaluated and placed within a theoretical framework depicted in Fig. 1.
doi:10.1016/S0079-6123(07)00020-9
PMCID: PMC2657600  PMID: 18394484
attention; capacity of working memory; control of attention; decay of short-term memory; focus of attention; long-term memory; short-term memory; working memory
19.  Eye movements in Visual Search Indicate Impaired Saliency Processing in Parkinson's Disease 
Progress in brain research  2008;171:559-562.
Previous studies have produced contradictory evidence on the nature of the visual search impairment in patients with Parkinson's Disease (PD). Eye movements were measured during multi-target search in 9 individuals with mild to moderate PD. Subjects were asked to click on a response button whenever they judged they were fixating a target for the first time. Compared to age-matched healthy volunteers, PD patients were impaired at efficient search (detecting ‘+’s amongst ‘Ls’) but not inefficient search (‘T's amongst ‘Ls’). However, these patients had normal memory for locations as indexed by their rate of re-clicking on previously inspected locations. We suggest that the pattern of gaze for efficient search may reflect impaired saliency processing in PD.
doi:10.1016/S0079-6123(08)00679-1
PMCID: PMC2655700  PMID: 18718353
Visual Search; Sacccades; Parkinson's Disease; Saliency
20.  Short-latency disparity vergence eye movements: dependence on the preëxisting vergence angle 
Progress in brain research  2008;171:245-251.
We recorded the vergence eye movements that are elicited at ultra-short latencies when binocular disparities are applied to large-field patterns (Busettini et al., 1996) and determined their dependence on the preëxisting vergence angle (PVA). The search coil technique was used to record the movements of both eyes in four healthy subjects (two with presbyopia). Using dichoptic viewing, the two eyes saw identical images each consisting of a fixation cross at the center of a random dot pattern in a circular aperture. The subject fixated the crosses and then the images (crosses, random dots, windows) moved horizontally (1.5°/s) in opposite directions so as to bring the eyes to the desired horizontal vergence position without changing the accommodation demand. After a further 800-1200 ms to permit fusion at this new vergence angle (now, the PVA), a disparity step was applied and, 200ms later, the screen changed to uniform gray, marking the end of the trial. The disparity steps could have one of 6 magnitudes and four directions (crossed, uncrossed, right-hyper, left-hyper) while the PVA was varied systematically. The horizontal and vertical DVRs of one of the presbyopes consistently showed robust linear dependence on the PVA (r2>0.96). The horizontal DVRs of the other three subjects showed no sensitivity to the PVA and their vertical DVRs showed only very weak dependence. The experiment was repeated on one of the non-presbyopes after cycloplegia, but the outcome was the same, indicating that the negative findings were not due to the influence of the vergence-accommodation response. Our data indicate that the DVRs can be scaled by the PVA, but most subjects do not show this effect, perhaps because they relied on other distance cues that are uninformative in our experimental situation.
doi:10.1016/S0079-6123(08)00634-1
PMCID: PMC2562629  PMID: 18718308
Disparity Vergence Eye Movements
21.  Oblique Gaze Shifts: Head Movements Reveal New Aspects of Component Coupling 
Progress in brain research  2008;171:323-330.
When the head is prevented from moving, it has been clearly demonstrated that the horizontal and vertical components of oblique saccades are not independently produced. The duration of the smaller of the two components is stretched in time to match the duration of the larger component. Several hypotheses have been proposed and each can account for the observed interaction between horizontal and vertical saccade components. When the head is free to move, gaze shifts can be accomplished by combining eye and head movements. During repeated gaze shifts of the same amplitude, as head contribution increases, saccade amplitude declines but saccade duration increases. Thus, the expected relationship between duration and amplitude of saccadic eye movements can be reversed. We have used this altered relationship to determine whether the duration of the vertical saccade component is affected by the amplitude or the duration of the horizontal component. We find that the relative amplitudes of horizontal and vertical saccades cannot account for the observed temporal stretching: vertical component duration increases despite a decrease in the amplitude of the horizontal component. These results are likely inconsistent with models that rely on calculating the vector or relative component amplitudes to account for component stretching.
doi:10.1016/S0079-6123(08)00647-X
PMCID: PMC2605951  PMID: 18718321
22.  Assessment of neuroprotection in the retina with DARC 
Progress in brain research  2008;173:437-450.
Currently, assessment of new drug efficacy in glaucoma relies on conventional perimetry to monitor visual field changes. However, visual field defects cannot be detected until 20-40% of retinal ganglion cells (RGCs), the key cells implicated in the development of irreversible blindness in glaucoma, have been lost. We have recently developed a new, noninvasive real-time imaging technology, which is named DARC (detection of apoptosing retinal cells), to visualize single RGC undergoing apoptosis, the earliest sign of glaucoma. Utilizing fluorescently labeled annexin 5 and confocal laser scanning ophthalmoscopy, DARC enables evaluation of treatment effectiveness by monitoring RGC apoptosis in the same living eye over time. Using DARC, we have assessed different neuroprotective therapies in glaucoma-related animal models and demonstrated DARC to be a useful tool in screening neuroprotective strategies. DARC will potentially provide a meaningful clinical end point that is based on the direct assessment of the RGC death process, not only being useful in assessing treatment efficacy, but also leading to the early identification of patients with glaucoma. Clinical trials of DARC in glaucoma patients are due to start in 2008.
doi:10.1016/S0079-6123(08)01130-8
PMCID: PMC2603274  PMID: 18929126
DARC; RGC apoptosis; glaucoma; neuroprotection; glutamate modulation; targeting Aβ pathway; coenzyme Q10
23.  Nonapeptides and the Evolutionary Patterning of Sociality 
Progress in brain research  2008;170:3-15.
Neuropeptides of the arginine vastocin (AVT) family, which include the mammalian peptides arginine vasopressin (AVP) and oxytocin (OXT), comprise neuroendocrine circuits that range from being evolutionarily conserved to evolutionarily diverse. For instance, the functions and anatomy of the AVT/AVP projections to the pituitary (which arise in the preoptic area and hypothalamus) are strongly conserved, whereas those of extrahypothalamic AVT/AVP circuits are species-specific and change rapidly over evolutionary time. AVT/AVP circuits arising in the medial bed nucleus of the stria terminalis (BSTm) exhibit species-specific evolution in relation to mating system in mammals (monogamous versus non-monogamous) and sociality in songbirds (gregarious versus relatively asocial). In estrildid songbirds, AVT neurons in the BSTm increase their Fos expression only in response to “positively-valenced” social stimuli (stimuli that normally elicit affiliation), whereas “negative” stimuli (which elicit aggression or aversion) produce no response or even suppress Fos expression. Relative to territorial species, gregarious species show 1) greater social induction of Fos within AVT neurons, 2) a higher baseline of Fos expression in AVT neurons, 3) more AVT neurons in the BSTm, and 4) a higher density of V1a-like binding sites in the lateral septum. Furthermore, septal AVT infusions inhibit resident-intruder aggression, but facilitate aggression that is motivated by mate competition (an affiliative context). The functional profile of the BSTm AVT neurons is therefore quite distinct from that of hypothalamic AVT/AVP neurons, particularly those of the paraventricular nucleus (PVN), which are classically stress-responsive. This is paradoxical, given that AVT/AVP projections from the PVN and BSTm likely overlap. Despite this overlap, each AVT/AVP cell group should produce a distinct pattern of modulation across brain regions. Relative weighting of hypothalamic and BSTm nonapeptide circuitries may therefore be an important determinant of approach-avoidance behavior, and may be a prime target of natural selection related to sociality.
doi:10.1016/S0079-6123(08)00401-9
PMCID: PMC2570786  PMID: 18655867
vasotocin; vasopressin; oxytocin; isotocin; evolution; social behavior
24.  Human ocular following: evidence that responses to large-field stimuli are limited by local and global inhibitory influences 
Progress in brain research  2008;171:237-243.
Large-field visual motion elicits tracking eye movements at ultra-short latency, often termed Ocular Following Responses (OFRs). We recorded the initial OFRs of 3 human subjects when vertical sine-wave gratings were subject to horizontal motion in the form of successive ¼-wavelength steps. The gratings could occupy the full screen (45° wide, 30° high) or a number of horizontal strips, each 1° high and extending the full width of the display. These strips were always equally spaced vertically. In a first experiment, the gratings always had a contrast of 32%. Increasing the number of strips could reduce the response latency by up to 20 ms, so the magnitude of the initial OFRs was estimated from the change in eye position over the initial open-loop period measured with respect to response onset. A single (centered) strip (covering 3.3% of the screen) always elicited robust OFRs, and 3 strips (10% coverage) were sufficient to elicit the maximum OFR. Increasing the number of strips to 15 (50% coverage) had little impact, i.e., responses had asymptoted, and further increasing the coverage to 100% (full screen image) actually decreased the OFR so that it was now less than that elicited with only 1 strip. In a second experiment, the contrast of the gratings could be fixed at one of four levels ranging from 8% to 64% and the OFR showed essentially the same pattern of dependence on screen coverage except that the lower the contrast, the lower the level at which the response asymptoted. This indicated that the asymptote was not due simply to some upper limit on the magnitude of the eye movement or the underlying motion signals. We postulate that this asymptote is the result of normalization due to global divisive inhibition, which has often been described in visual-motion-selective neurons in the cortex. We further suggest that the decrease in the OFR when the image filled the screen was due to the increased continuity of the gratings which we postulate would favor the local inhibitory surround mechanisms over the central excitatory ones. This study indicates that robust OFRs can be elicited by much smaller motion stimuli than is commonly supposed and that introducing spatial discontinuities can increase the efficacy of the motion stimuli even while decreasing the area stimulated.
doi:10.1016/S0079-6123(08)00633-X
PMCID: PMC2562005  PMID: 18718307
Ocular Following Response (OFR); Response normalization; Surround inhibition
25.  The Parvocellular Vasopressinergic System and Responsiveness of the Hypothalamic Pituitary Adrenal Axis during Chronic Stress 
Progress in brain research  2008;170:29-39.
Vasopressin (VP) secreted from parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) stimulates pituitary ACTH secretion, through interaction with receptors of the V1b subtype (V1bR) in the pituitary corticotroph, mainly by potentiating the stimulatory effects of corticotrophin releasing hormone (CRH). Chronic stress paradigms associated with corticotroph hyperresponsiveness lead to preferential expression of hypothalamic VP over CRH and upregulation of pituitary V1bR, suggesting that VP has a primary role during adaptation of the hypothalamic pituitary adrenal (HPA) axis to long-term stimulation. However, studies using pharmacological of genetic ablation of V1b receptors have shown that VP is required for full ACTH responses to some stressors, but not for the sensitization of ACTH responses to a novel stress observed during chronic stress. Studies using minipump infusion of a peptide V1 antagonist in long-term adrenalectomized rats have revealed that VP mediates proliferative responses in the pituitary. Nevertheless, only a minor proportion of cells undergoing mitogenesis co-express markers for differentiated corticotrophs or precursors, suggesting that new corticotrophs are recruited from yet undifferentiated cells. The overall evidence supports a limited role of VP regulating acute ACTH responses to some acute stressors and points to cell proliferation and pituitary remodeling as alternative roles for the marked increases in parvocellular vasopressinergic activity during prolonged activation of the HPA axis.
doi:10.1016/S0079-6123(08)00403-2
PMCID: PMC2536760  PMID: 18655869
vasopressin; corticotrophin releasing hormone; ACTH secretion; hypothalamic paraventricular nucleus; stress; adrenalectomy; pituitary mitogenesis

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