Lateral inhibition in V1 controls neural & perceptual contrast sensitivity.

Lateral inhibition is a central principle for sensory system function. It is thought to operate by the activation of inhibitory neurons that restrict the spatial spread of sensory excitation. Much work on the role of inhibition in sensory systems has focused on visual cortex; however, the neurons, computations, and mechanisms underlying cortical lateral inhibition remain debated, and its importance for visual perception remains unknown. Here, we tested how lateral inhibition from PV or SST neurons in mouse primary visual cortex (V1) modulates neural and perceptual sensitivity to stimulus contrast. Lateral inhibition from PV neurons reduced neural and perceptual sensitivity to visual contrast in a uniform subtractive manner, whereas lateral inhibition from SST neurons more effectively changed the slope (or gain) of neural and perceptual contrast sensitivity. A neural circuit model identified spatially extensive lateral projections from SST neurons as the key factor, and we confirmed this with direct subthreshold measurements of a larger spatial footprint for SST versus PV lateral inhibition. Together, these results define cell-type specific computational roles for lateral inhibition in V1, and establish their unique consequences on sensitivity to contrast, a fundamental aspect of the visual world.

Optimizing intact skull intrinsic signal imaging for subsequent targeted electrophysiology across mouse visual cortex.

Understanding brain function requires repeatable measurements of neural activity across multiple scales and multiple brain areas. In mice, large scale cortical neural activity evokes hemodynamic changes readily observable with intrinsic signal imaging (ISI). Pairing ISI with visual stimulation allows identification of primary visual cortex (V1) and higher visual areas (HVAs), typically through cranial windows that thin or remove the skull. These procedures can diminish long-term mechanical and physiological stability required for delicate electrophysiological measurements made weeks to months after imaging (e.g., in subjects undergoing behavioral training). Here, we optimized and directly validated an intact skull ISI system in mice. We first assessed how imaging quality and duration affect reliability of retinotopic maps in V1 and HVAs. We then verified ISI map retinotopy in V1 and HVAs with targeted, multi-site electrophysiology several weeks after imaging. Reliable ISI maps of V1 and multiple HVAs emerged with ~ 60 trials of imaging (65 ± 6 min), and these showed strong correlation to local field potential (LFP) retinotopy in superficial cortical layers (r2 = 0.74-0.82). This system is thus well-suited for targeted, multi-area electrophysiology weeks to months after imaging. We provide detailed instructions and code for other researchers to implement this system.

Spatial modulation of dark versus bright stimulus responses in the mouse visual system.

A fundamental task of the visual system is to respond to both increases and decreases of luminance with action potentials (ON and OFF responses1-4). OFF responses are stronger, faster, and more salient than ON responses in primary visual cortex (V1) of both cats5,6 and primates,7,8 but in ferrets9 and mice,10 ON responses can be stronger, weaker,11 or balanced12 in comparison to OFF responses. These discrepancies could arise from differences in species, experimental techniques, or stimulus properties, particularly retinotopic location in the visual field, as has been speculated;9 however, the role of retinotopy for ON/OFF dominance has not been systematically tested across multiple scales of neural activity within species. Here, we measured OFF versus ON responses across large portions of visual space with silicon probe and whole-cell patch-clamp recordings in mouse V1 and lateral geniculate nucleus (LGN). We found that OFF responses dominated in the central visual field, whereas ON and OFF responses were more balanced in the periphery. These findings were consistent across local field potential (LFP), spikes, and subthreshold membrane potential in V1, and were aligned with spatial biases in ON and OFF responses in LGN. Our findings reveal that retinotopy may provide a common organizing principle for spatial modulation of OFF versus ON processing in mammalian visual systems.

A novel device for real-time measurement and manipulation of licking behavior in head-fixed mice.

The mouse has become an influential model system for investigating the mammalian nervous system. Technologies in mice enable recording and manipulation of neural circuits during tasks where they respond to sensory stimuli by licking for liquid rewards. Precise monitoring of licking during these tasks provides an accessible metric of sensory-motor processing, particularly when combined with simultaneous neural recordings. There are several challenges in designing and implementing lick detectors during head-fixed neurophysiological experiments in mice. First, mice are small, and licking behaviors are easily perturbed or biased by large sensors. Second, neural recordings during licking are highly sensitive to electrical contact artifacts. Third, submillisecond lick detection latencies are required to generate control signals that manipulate neural activity at appropriate time scales. Here we designed, characterized, and implemented a contactless dual-port device that precisely measures directional licking in head-fixed mice performing visual behavior. We first determined the optimal characteristics of our detector through design iteration and then quantified device performance under ideal conditions. We then tested performance during head-fixed mouse behavior with simultaneous neural recordings in vivo. We finally demonstrate our device's ability to detect directional licks and generate appropriate control signals in real time to rapidly suppress licking behavior via closed-loop inhibition of neural activity. Our dual-port detector is cost effective and easily replicable, and it should enable a wide variety of applications probing the neural circuit basis of sensory perception, motor action, and learning in normal and transgenic mouse models. NEW & NOTEWORTHY Mice readily learn tasks in which they respond to sensory cues by licking for liquid rewards; tasks that involve multiple licking responses allow study of neural circuits underlying decision making and sensory-motor integration. Here we design, characterize, and implement a novel dual-port lick detector that precisely measures directional licking in head-fixed mice performing visual behavior, enabling simultaneous neural recording and closed-loop manipulation of licking.

Interleukin-6 increases the expression of key proteins associated with steroidogenesis in human NCI-H295R adrenocortical cells.

Mechanisms of interleukin-6 (IL-6)-induced cortisol release (CR) were investigated by exposing H295R cells to IL-6 and determining mRNA/protein expression (PCR/western blots) for steroidogenic enzymes (SE), steroidogenic acute regulatory protein (StAR), steroidogenic factor-1 (SF-1) (enhances SE/StAR expression), activator protein 1 (AP-1) (regulates SE/StAR expression) and adrenal hypoplasia congenita-like protein (DAX-1) (inhibits SE/StAR expression). Promoter activity of StAR (SPA) was measured by a luciferase-coupled promoter. Cortisol release was increased by 10ng/mL IL-6 (24h P<0.01). Proteins/mRNAs (StAR, cholesterol side chain cleavage enzyme, SF-1, AP-1) and SPA were increased by IL-6 (60min 1-50ng/mL IL-6; 5ng/mL IL-6 30-120min P<0.05). Four other SE proteins/mRNAs were also increased by 10ng/mL IL-6 (60min P<0.01). Protein/mRNA for DAX-1 was decreased by IL-6 (60min 1-50ng/mL IL-6; 5ng/mL IL-6 30-120min P<0.01). Phosphorylation of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) was increased by IL-6 (JAK2 60min 1-50ng/mL IL-6; 10ng/mL IL-6 5-60min P<0.05; STAT1 and STAT3 60min 10ng/mL IL-6 P<0.01). Inhibition of JAK/STAT with AG490 (10µM) or piceatannol (50µM) blocked (P<0.01 10ng/mL IL-6vs. IL-6 plus AG490 or piceatannol) IL-6-induced increases in SPA and StAR mRNA. In summary, IL-6-induced CR may be facilitated by increased StAR and SE mediated by increased SF-1 and AP-1, decreased DAX-1, and increased phosphorylation of JAK/STAT.

Using the Utah Population Database to assess familial risk of primary open angle glaucoma.

PURPOSE: Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness in the elderly. Previous epidemiological studies have identified family history, ethnic origin, age, high intraocular pressure and diabetes mellitus as risk factors. However, it is difficult to assess the extent family history plays in this disease process. The Utah Population Database (UPDB), created by the University of Utah, has recently become a resource for which greater than 9 million records are available for use. The UPDB is divided into two major data sets from which family members can be identified, namely 1.6 million genealogy records and 2 million Utah birth certificates. This study utilizes these resources to assess the familial risk of POAG within the Utah Population. METHODS: The University of Utah's hospital and clinic records were searched for patients with primary and chronic open angle glaucoma (ICD9 codes 365.04 and 365.11) between the years 1995 and 2005. A case-control analysis was then performed with specialized UPDB software that was modified to constrain the control and pedigree populations to over 1 million University of Utah-UPDB linked records. Controls were matched to cases by gender and birth year (±2.5years) with only one control being used per case. Population-attributable risk (PAR) to familial factors and relative risk (RR) were computed using conditional logistic regression (CLR). RESULTS: From the original 1.5 million medical records, 6198 patients with glaucoma were identified. Of these, 3391 met the inclusion criteria, which required patients to have at least one parent or one child in the UPDB. The PAR in this population was found to be 0.20, indicating 20% of the risk for glaucoma is attributable to genetic factors. CLR computations also showed a significantly increased relative risk (p<0.05) in first cousins (RR=1.45 (95% confidence interval (CI) 1.16-1.8)), second cousins (RR=1.19 (95% CI 1.08-1.32)), siblings (RR=3.76 (95% CI 2.66-5.31)), parents (RR=6.25 (95% CI 3.94-9.9)) and children (RR=6.77 (95% CI 3.39-13.5)). CONCLUSIONS: Based on these familial data, there is a significantly higher prevalence of glaucoma in both first and second generation relatives of those affected as compared to relatives in the control group. When compared with other epidemiologic studies, such as an analysis of first-degree relatives of patients from the Rotterdam study, which showed a PAR of 16%, our study actually demonstrates a greater familial contribution to glaucoma. The UPDB is a valuable and unique resource providing a large population from which to analyze the familial risk of glaucoma.

Increased intracranial pressure in a case of pediatric multiple sclerosis.

A 15-year-old girl presented to our emergency department with dizziness, anorexia, nausea, and malaise. Clinical examination and magnetic resonance imaging studies showed characteristic features of multiple sclerosis. Surprisingly, a diagnostic lumbar puncture showed significant intracranial hypertension in addition to numerous oligoclonal bands, elevated immunoglobulin G index and immunoglobulin G/albumin ratio in the cerebrospinal fluid. It is proposed that a large burden of active demyelinating disease may cause increased intracranial pressure, thus providing an additional sound rationale for prompt therapeutic administration of intravenous high-dose steroids.

Higher levels of estradiol replacement correlate with better spatial memory in surgically menopausal young and middle-aged rats.

The current study investigated whether, for spatial reference memory, age impacts (1) sensitivity to surgical ovarian hormone loss (Ovx), (2) response to estradiol therapy (ET), and (3) the relation between circulating estradiol levels and memory scores in ovary-intact sham and Ovx plus ET rats. Young, middle-aged and aged Fischer-344 rats received sham, Ovx or Ovx plus ET treatments, and were then tested on the Morris maze. After the last test trial, a probe trial was given whereby the platform was removed. Circulating estradiol levels were then determined and correlated with performance. In Study 1, Ovx facilitated learning on day one, but impaired performance after day one, in young rats. Ovx did not influence performance in middle-aged rats. In young and middle-aged Ovx rats, ET enhanced performance with higher exogenous estradiol levels correlating with better performance during testing and the probe trial. There was no relationship between endogenous estradiol levels and performance in sham young or middle-aged rats. Study 2 showed that, like middle-aged rats, aged rats were not impacted by Ovx. Further, for aged Ovx rats, the ET regimen that was beneficial at earlier ages was no longer effective during test trials, and had only minor benefits for platform localization as assessed by the probe trial. Collectively, the findings suggest that the effects of Ovx as well as responsivity to the currently utilized ET regimen changes with age. Further, there appears to be a distinction between sensitivity to Ovx and responsiveness to ET after Ovx for spatial reference memory performance.

Age-dependent loss of NGF signaling in the rat basal forebrain is due to disrupted MAPK activation.

The loss of nerve growth factor (NGF) and its high affinity receptor TrkA has been implicated in the loss of cholinergic tone and function in Alzheimer's disease (AD) and normal aging. We employed an animal model of aging, the aged rat, which also exhibits memory loss and NGF alterations. Basal forebrain TrkA levels increased after injection of NGF in the hippocampus within 1h in young rats, but this response was diminished in aged animals as determined by Western blot analysis. Further, NGF activated MAPK pathways without changing total ERK levels and the activation of these pathways was also diminished in aged animals. The exogenous NGF injection did not appear to activate the PI-3K pathway or alter total levels of Akt significantly. These data shed light on mechanisms of NGF signaling in the CNS, and alterations in this signaling cascade associated with age and memory loss. These findings might lead to development of novel treatment therapies for the memory loss associated with AD and other age-associated neurodegenerative diseases.

Nerve growth factor in treatment and pathogenesis of Alzheimer's disease.

The etiology of Alzheimer's disease (AD) is still unknown. In addition, this terrible neurodegenerative disease will increase exponentially over the next two decades due to longer lifespan and an aging "baby-boomer" generation. All treatments currently approved for AD have moderate efficacy in slowing the rate of cognitive decline in patients, and no efficacy in halting progression of the disease. Hence, there is an urgent need for new drug targets and delivery methods to slow or reverse the progression of AD. One molecule that has received much attention in its potential therapeutic role in AD is nerve growth factor (NGF). This review will demonstrate data from humans and animals which promote NGF as a potential therapeutic target by (1) outlining the hypothesis behind using NGF for the treatment of AD, (2) reviewing both the normal and AD altered signaling pathways and effects of NGF in the central nervous system (CNS), and (3) examining the results of NGF treatment obtained from animal models of AD and AD patients.

ERK-mediated NGF signaling in the rat septo-hippocampal pathway diminishes with age.

RATIONALE: Degeneration of basal forebrain cholinergic neurons (BFCNs) plays an important role in aging and Alzheimer's disease (AD) pathology. This degeneration may be a result of disrupted nerve growth factor (NGF) signaling. Aged rats have memory deficits, BFCN degeneration, and disrupted NGF signaling. OBJECTIVE: In this study we identify a rapid NGF signaling pathway in BFCNs and the second messenger system associated with that signaling. We also identify age-dependent alterations in this signaling pathway. MATERIALS AND METHODS: After cognitive assessment using the Morris water maze, rats were given an intra-hippocampal NGF injection. Basal forebrain immunohistochemical analysis, confocal microscopy, and inhibitor studies were performed. RESULTS: An increase in immunoreactivity for the NGF receptor TrkA was found in cell bodies of BFCNs 15 min and 1 h post-NGF injection. Immunohistochemistry studies with phospho-ERK and phospho-AKT antibodies showed that this rapid signaling occurred through MAP kinase, but not PI-3 kinase pathways. MAPK inhibitor studies attenuated the NGF-induced effects. Both TrkA and phospho-ERK (extracellular signal-regulated kinase) immunoreactivities were diminished in aged rats and phospho-ERK immunoreactivity-correlated with aged rat performance in the Morris water maze. CONCLUSIONS: Rapid NGF signaling likely occurs in the rat CNS through the MAPK signaling pathway. This rapid signaling pathway is diminished in aged rats compared to young ones and may contribute to memory deficits observed in aged rats. As cholinergic degeneration coupled with altered levels of NGF and TrkA receptors are also seen in human aging and AD, ERK-related dysfunction may be relevant in human conditions as well.

Pediatric superior vena cava syndrome: assessment at low radiation dose 64-slice CT angiography.

We report a case of an 8-year-old boy with a history of aortopexy for aortic compression and multiple venous thrombosis. A 64-slice multidetector-row computed tomography examination was performed to evaluate the cause of esophageal varices and the extent of previously reported thrombi. Despite extremely low radiation dose settings, the 64-slice computed tomography angiography was fully diagnostic and showed discontinuity of the superior vena cava and brachiocephalic veins. In addition, the azygous system and large collateral vessels across the anterior, medial, and posterior mediastinum and chest wall were observed. This case shows that in pediatric patients complicated vascular pathology can reliably be assessed and radiation exposure can be safely minimized.

Altered NGF response but not release in the aged septo-hippocampal cholinergic system.

An important aspect of aging and Alzheimer's disease (AD) pathology includes the degeneration of basal forebrain cholinergic neurons (BFCNs), possibly due to disrupted nerve growth factor (NGF) signaling. Previous studies on disrupted NGF signaling have focused on changes in retrograde transport. This study focuses on two other possible mechanisms for loss of trophic support: diminished release of NGF from hippocampal neurons or diminished TrkA receptor response of BFCNs to NGF. We measured NGF levels in the effluent of hippocampal slices from young and aged rats in response to potassium chloride and glutamate. We found that release of NGF was not altered in aged hippocampal slices compared to slices from young controls. To measure the in situ response of the BFCNs to NGF, we injected NGF intraparenchymally into the right hippocampus of young and aged rats. Injections of cytochrome C served as controls. Fifteen minutes post-administration, a dramatic increase in TrkA immunoreactivity was found in the cell bodies of medial septal neurons. We found that this rapid response was blunted in aged rats compared to young adult controls. To determine whether retrograde transport was necessary for this rapid response, we injected colchicine prior to NGF injection. The NGF-induced upregulation was not blocked by colchicine, suggesting that this acute response was not dependent on classical retrograde transport. Since cholinergic degeneration coupled with altered levels of NGF and TrkA receptors are also seen in human aging and AD, the loss of acute responsivity to NGF in the BFCNs may also play a role in these processes.

Ovarian hormones and cognition in the aged female rat: II. progesterone supplementation reverses the cognitive enhancing effects of ovariectomy.

The authors hypothesized that the progesterone component of some hormone replacement therapies in women is detrimental to cognition. A previous study showed that ovariectomy (ovx) in aged rats enhanced spatial working memory and decreased elevated progesterone levels. The current study evaluated whether progesterone administration counteracts these cognitive enhancing effects of ovx. Aged sham and aged ovx rats given progesterone exhibited compromised learning of the working and reference memory components of the task, and made more working memory errors on the latter testing days compared with aged ovx rats not given progesterone. Results suggest that whereas ovx of the aged female rat enhances learning and the ability to handle numerous items of spatial working memory information, progesterone is detrimental to these aspects of performance. These findings may speak to studies in menopausal women which suggest that combination hormone therapies have a negative impact on cognition.