John Gigg

Melanopsin Contributions to Irradiance Coding in the Thalamo-Cortical Visual System

Neurophysiological and anatomical studies identify melanopsin expressing retinal ganglion cells (mRGCs) as a major source of information in the mouse visual system.

Metabotropic glutamate receptor activation and blockade: their role in long-term potentiation, learning and neurotoxicity

Metabotropic glutamate receptors represent a fairly recent addition to the family of glutamate receptors. These receptors have the distinguishing feature of being coupled to G-proteins rather than ion channels and they appear to have a variety of functional characteristics. These receptors play a vital role, for example, in the induction and maintenance of long-term potentiation, the most popular current model of the biological correlates of learning and memory. Blockade of metabotropic glutamate receptors prevents long-term potentiation induction and learning in a variety of tasks in different species. Chronic metabotropic glutamate receptor activation is also associated with neurodegeneration and selective neuronal loss when agonists of these receptors are injected in high concentrations directly into the brain. Metabotropic glutamate receptors also play a role in the normal development of the nervous system and these sites within the central nervous system offer possible routes for drug therapies; selective receptor antagonists, for example, may prove to have the very desirable feature of endowing neuroprotection during ischaemic episodes whilst allowing normal excitatory neurotransmission to occur.

Interaction between paired-pulse facilitation and long-term potentiation in the projection from hippocampal area CA1 to the subiculum.

Studies of the interaction between long-term potentiation (LTP) and paired-pulse facilitation (PPF) may throw light on the role of presynaptic factors in LTP. We examine here, for the first time, the nature of PPF in the CA1-subiculum projection. PPF peaks at a 50 ms interstimulus interval (ISI) and is evident at ISIs from 10 to 500 ms. There is no PPF effect at a 1000 ms ISI. PPF decreases in magnitude post-LTP induction across the middle range of ISI values tested (30, 50 and 100 ms). There is a positive correlation between initial PPF values and LTP; this correlation increases as the ISI increases. Initial values and the change in PPF post-LTP are also negatively correlated.

Neurophysiology and neuropharmacology of projections from entorhinal cortex to striatum in the rat.

We studied projections from the entorhinal cortex (Ent) to the striatum in anesthetized rats using extra- and intracellular recording and multibarrel iontophoresis. The majority of recording were from the caudate-putamen (CPu) and core of the nucleus accumbens (AcbC). Electrical stimulation of the Ent evoked synaptic responses in 77% of tests with AcbC neurons and 48% of tests with CPu neurons. In the case of AcbC neurons, 61% of these tests proved to be excitatory and were often followed by inhibitory phases. In contrast to this, only 18% of tests from CPu neurons were excitatory. Intracellular HRP labeling showed that responsive cells were medium spiny neurons. During iontophoretic experiments, application of the glutamatergic AMPA antagonist DNQX could selectively decrease or block excitatory responses. The GABAA antagonist bicuculline methiodide increased cellular firing rates and could reveal excitatory responses, suggesting block of a short-latency, short-duration inhibitory component. Ejection of the GABAB antagonist CGP-35348 could attenuate a later, longer-duration component of inhibition. The results indicate that the Ent excites striatal neurons at least in part by glutamatergic receptors and suggest that this excitation is followed by secondary prolonged GABAergic inhibition.

The projection from hippocampal area CA1 to the subiculum sustains long- term potentiation

LONG-TERM potentiation (LTP) is a popular model of the synaptic plasticity which may be engaged by the biological processes underlying learning and memory. Most available studies of LTP have concentrated on the analysis of LTP occurring in ‘early’ components of the hippocampal circuit (for example, dentate gyrus and area CA1). We examine here, for the first time, LTP as it occurs in the massive, unidirectional projection from CA1 to the subiculum in vivo. We show that this projection sustains high-frequency stimulus-induced LTP (10 trains of 20 stimuli at 20 0 Hz; intertrain interval 2 s; LTP 181 ± 9% at 30 min post-LTP induction). In addition, input-output (I/O) curves show a leftward shift for all stimulation values.

Responses of rat subicular neurons to convergent stimulation of lateral entorhinal cortex and CA1 in vivo

There has been little electrophysiological examination of the afferent projection from lateral entorhinal cortex to dorsal subiculum. Here we provide evidence that synaptic inputs from lateral entorhinal cortex and CA1 converge onto single dorsal subicular neurons in vivo. Subicular responses to CA1 stimulation consisted of excitation and/or long-duration inhibition. Neurons excited by CA1 activation usually showed inhibition to entorhinal stimulation. The latter inhibition was usually of short duration, however, long duration inhibition was seen in a significant proportion of responses. Entorhinal stimulation produced excitatory responses in four bursting cells and it was these cells that also tended to show the longest inhibition. Only bursting cells could be driven antidromically by entorhinal stimulation. Biocytin-filled multipolar and pyramidal cells displayed excitation-inhibition sequences to CA1 and inhibition to entorhinal stimulation. These data strongly suggest that subicular inhibitory neurons receive excitatory input from CA1 and display mutual inhibition. The source of entorhinal-evoked inhibition is less clear. The relative sparseness of observed entorhinal-evoked responses suggests that the input to dorsal subiculum from any one part of lateral entorhinal cortex is spatially restricted. These data show that excitation-inhibition sequences can be seen in subicular pyramidal and multipolar cells and that single subicular neurons receive convergent inputs from CA1 and entorhinal cortex. We show for the first time that bursting cells can be driven both orthodromically and antidromically by direct entorhinal stimulation. These data support the existence of a reciprocal excitatory connection between lateral entorhinal cortex and dorsal subiculum and suggest further that this connection may involve only bursting subicular neurons.

Inverse Current Source Density Method in Two Dimensions: Inferring Neural Activation from Multielectrode Recordings

The recent development of large multielectrode recording arrays has made it affordable for an increasing number of laboratories to record from multiple brain regions simultaneously. The development of analytical tools for array data, however, lags behind these technological advances in hardware. In this paper, we present a method based on forward modeling for estimating current source density from electrophysiological signals recorded on a two-dimensional grid using multi-electrode rectangular arrays. This new method, which we call two-dimensional inverse Current Source Density (iCSD 2D), is based upon and extends our previous one- and three-dimensional techniques. We test several variants of our method, both on surrogate data generated from a collection of Gaussian sources, and on model data from a population of layer 5 neocortical pyramidal neurons. We also apply the method to experimental data from the rat subiculum. The main advantages of the proposed method are the explicit specification of its assumptions, the possibility to include system-specific information as it becomes available, the ability to estimate CSD at the grid boundaries, and lower reconstruction errors when compared to the traditional approach. These features make iCSD 2D a substantial improvement over the approaches used so far and a powerful new tool for the analysis of multielectrode array data. We also provide a free GUI-based MATLAB toolbox to analyze and visualize our test data as well as user datasets.

Episodic-Like Memory for What-Where-Which Occasion is Selectively Impaired in the 3xTgAD Mouse Model of Alzheimer's Disease

Episodic memory loss is a defining feature of early-stage Alzheimers disease (AD). A test of episodic-like memory for the rat, the What-Where-Which occasion task (WWWhich), requires the association of object, location, and contextual information to form an integrated memory for an event. The WWWhich task cannot be solved by use of non-episodic information such as object familiarity and is dependent on hippocampal integrity. Thus, it provides an ideal tool with which to test capacity for episodic-like memory in the 3xTg murine model for AD. As this model captures much of the human AD phenotype, we hypothesized that these mice would show a deficit in the WWWhich episodic-like memory task. To test the specificity of any episodic-like deficit, we also examined whether mice could perform components of the WWWhich task that do not require episodic-like memory. These included object (Novel Object Recognition), location (Object Location Task, What-Where task), and contextual (What-Which) memory, as well as another three-component task that can be solved without reliance on episodic recall (What-Where-When; WWWhen). The results demonstrate for the first time that control 129sv/c57bl6 mice could form WWWhich episodic-like memories, whereas, 3xTgAD mice at 6 months of age were impaired. Importantly, while 3xTgAD mice showed some deficit on spatial component tasks, they were unimpaired in the more complex WWWhen combination task (which includes a spatial component and is open to non-episodic solutions). These results strongly suggest that AD pathology centered on the hippocampal formation mediates a specific deficit for WWWhich episodic-like memory in the 3xTgAD model.

Increased Hippocampal Excitability in the 3xTgAD Mouse Model for Alzheimer's Disease In Vivo

Mouse Alzheimers disease (AD) models develop age- and region-specific pathology throughout the hippocampal formation. One recently established pathological correlate is an increase in hippocampal excitability in vivo. Hippocampal pathology also produces episodic memory decline in human AD and we have shown a similar episodic deficit in 3xTg AD model mice aged 3–6 months. Here, we tested whether hippocampal synaptic dysfunction accompanies this cognitive deficit by probing dorsal CA1 and DG synaptic responses in anaesthetized, 4–6 month-old 3xTgAD mice. As our previous reports highlighted a decline in episodic performance in aged control mice, we included aged cohorts for comparison. CA1 and DG responses to low-frequency perforant path stimulation were comparable between 3xTgAD and controls at both age ranges. As expected, DG recordings in controls showed paired-pulse depression; however, paired-pulse facilitation was observed in DG and CA1 of young and old 3xTgAD mice. During stimulus trains both short-latency (presumably monosynaptic: ‘direct’) and long-latency (presumably polysynaptic: ‘re-entrant’) responses were observed. Facilitation of direct responses was modest in 3xTgAD animals. However, re-entrant responses in DG and CA1 of young 3xTgAD mice developed earlier in the stimulus train and with larger amplitude when compared to controls. Old mice showed less DG paired-pulse depression and no evidence for re-entrance. In summary, DG and CA1 responses to low-frequency stimulation in all groups were comparable, suggesting no loss of synaptic connectivity in 3xTgAD mice. However, higher-frequency activation revealed complex change in synaptic excitability in DG and CA1 of 3xTgAD mice. In particular, short-term plasticity in DG and CA1 was facilitated in 3xTgAD mice, most evidently in younger animals. In addition, re-entrance was facilitated in young 3xTgAD mice. Overall, these data suggest that the episodic-like memory deficit in 3xTgAD mice could be due to the development of an abnormal hyper-excitable state in the hippocampal formation.

Training-induced increases in neuronal activity recorded from the forebrain of the day-old chick are time dependent

Spontaneous neuronal bursting occurs in many areas of chick forebrain. Day-old chicks trained using a one-trial task to avoid a methylanthranilate-coated bead (methyl-chicks) show a significant increase in bursting when compared to chicks trained to peck a water-coated bead (water-chicks). This increase occurs in two forebrain areas: the intermediate medial hyperstriatum ventrale and the lobus parolfactorius. Bursting was recorded from the intermediate medial hyperstriatum ventrale of anaesthetized methyl- and water-chicks at eight time-points over the period 1-9 h post-test. Data merged over this period showed that methyl-chicks displayed an overall increase in bursting in both left and right hemispheres when compared to water-chicks. When burst activity was compared against time, bursting in methyl-chicks was significantly elevated only during the period 3-7 h post-test. Maximal bursting in methyl-chicks was seen 6-7 h post-test. These results suggest that the training-induced increase in bursting seen in the intermediate medial hyperstriatum ventrale of methyl-chicks is not a simple, generalized increase with time but rather has a significant temporal aspect. These results may have particular relevance to previously proposed models of memory formation in the chick.