Theta oscillations, timing and cholinergic modulation in the rodent hippocampal circuit

The medial temporal lobe (MTL) is crucial for episodic and spatial memory, and shows rhythmicity in the local field potential and neuronal spiking. Gamma oscillations (>40Hz) are mediatepd by local circuitry and interact with slower theta oscillations (6-10 Hz). Both oscillation frequencies are modulated by cholinergic input from the medial septum. Entorhinal grid cells fire when an animal visits particular locations in the environment arranged on the corners of tightly packed, equilateral triangles. Grid cells show phase precession, in which neurons fire at progressively earlier phases relative to theta oscillation as animals move through firing fields. This work focuses on the temporal organization of spiking and network rhythms, and their modulation by septal inputs, which are thought to be involved in MTL function. First, I recorded grid cells as rats explored open spaces and examined precession, previously only characterized on linear tracks, and compared it to predictions from models. I identified precession, including in conjunctive head-direction-by-grid cells and on passes that clipped the edge of the firing field. Secondly, I studied problems of measuring single neuron theta rhythmicity and developed an improved approach. Using the novel approach, I identified diverse modulation of rat medial entorhinal neurons’ rhythmic frequencies by running speed, independent from the modulation of firing rate by speed. Under pharmacological inactivation of the septum, rhythmic tuning was disrupted while rate tuning was enhanced. The approach also showed that available data is insufficient to prove that bat grid cells are arrhythmic due to low firing rates. In the final project, I optogenetically silenced cholinergic septal cells while recording from hippocampal area CA1. I identified changes in theta rhythmic currents and in theta-gamma coupling. This silencing disrupted performance when applied during the encoding phase of a delayed match to position task. These data support hypothetical roles of these rhythms in encoding and retrieval and suggest possible mechanisms for their modulation. Together, evidence from these projects suggests a role for theta in the function of spatial and episodic memory. These oscillations have important implications for communication and computation, and they can provide a substrate for efficient brain function

A dominant mutation in a neuronal acetylcholine receptor subunit leads to motor neuron degeneration in Caenorhabditis elegans

Inappropriate or excessive activation of ionotropic receptors can have dramatic consequences for neuronal function and, in many instances, leads to cell death. In Caenorhabditis elegans, nicotinic acetylcholine receptor (nAChR) subunits are highly expressed in a neural circuit that controls movement. Here, we show that heteromeric nAChRs containing the acr-2 subunit are diffusely localized in the processes of excitatory motor neurons and act to modulate motor neuron activity. Excessive signaling through these receptors leads to cell-autonomous degeneration of cholinergic motor neurons and paralysis. C. elegans double mutants lacking calreticulin and calnexin-two genes previously implicated in the cellular events leading to necrotic-like cell death (Xu et al. 2001)-are resistant to nAChR-mediated toxicity and possess normal numbers of motor neuron cell bodies. Nonetheless, excess nAChR activation leads to progressive destabilization of the motor neuron processes and, ultimately, paralysis in these animals. Our results provide new evidence that chronic activation of ionotropic receptors can have devastating degenerative effects in neurons and reveal that ion channel-mediated toxicity may have distinct consequences in neuronal cell bodies and processes

Cholinergic modulation of cognitive processing: insights drawn from computational models

Acetylcholine plays an important role in cognitive function, as shown by pharmacological manipulations that impact working memory, attention, episodic memory, and spatial memory function. Acetylcholine also shows striking modulatory influences on the cellular physiology of hippocampal and cortical neurons. Modeling of neural circuits provides a framework for understanding how the cognitive functions may arise from the influence of acetylcholine on neural and network dynamics. We review the influences of cholinergic manipulations on behavioral performance in working memory, attention, episodic memory, and spatial memory tasks, the physiological effects of acetylcholine on neural and circuit dynamics, and the computational models that provide insight into the functional relationships between the physiology and behavior. Specifically, we discuss the important role of acetylcholine in governing mechanisms of active maintenance in working memory tasks and in regulating network dynamics important for effective processing of stimuli in attention and episodic memory tasks. We also propose that theta rhythm plays a crucial role as an intermediary between the physiological influences of acetylcholine and behavior in episodic and spatial memory tasks. We conclude with a synthesis of the existing modeling work and highlight future directions that are likely to be rewarding given the existing state of the literature for both empiricists and modelers

A conserved dopamine-cholecystokinin signaling pathway shapes context-dependent Caenorhabditis elegans behavior

An organism\u27s ability to thrive in changing environmental conditions requires the capacity for making flexible behavioral responses. Here we show that, in the nematode Caenorhabditis elegans, foraging responses to changes in food availability require nlp-12, a homolog of the mammalian neuropeptide cholecystokinin (CCK). nlp-12 expression is limited to a single interneuron (DVA) that is postsynaptic to dopaminergic neurons involved in food-sensing, and presynaptic to locomotory control neurons. NLP-12 release from DVA is regulated through the D1-like dopamine receptor DOP-1, and both nlp-12 and dop-1 are required for normal local food searching responses. nlp-12/CCK overexpression recapitulates characteristics of local food searching, and DVA ablation or mutations disrupting muscle acetylcholine receptor function attenuate these effects. Conversely, nlp-12 deletion reverses behavioral and functional changes associated with genetically enhanced muscle acetylcholine receptor activity. Thus, our data suggest that dopamine-mediated sensory information about food availability shapes foraging in a context-dependent manner through peptide modulation of locomotory output

Beyond drug screens: A genetic approach to C. elegans Cholinergic signaling

Genes that are involved in localization or modulation of neurotransmitter receptors are difficult to identify. We generated a C. elegans strain expressing a mutated, hyperactivitied acetylcholine receptor. These animals display a dramatic movement phenotype, as well as mislocalization of a related receptor. Our genetic screen for suppressors of the movement phenotype isolated 15 suppressors, many of which would not have been isolated using traditional methods. We believe that this strategy will find novel factors that play important roles in cholinergic signaling

EduVentures WebExpedition

This project, sponsored by EduVentures and the National Museum of Namibia, sought to increase Namibian secondary students' awareness of biodiversity by creating and deploying a computer game called WebExpedition. We received input from teachers and students to optimize the game's usefulness and effectiveness, and performed trial runs with Namibian students. The game teaches students about scientific classification of organisms, and allows students to connect animals and plants to their habitats in Namibia

The functional organization of excitatory synaptic input to place cells.

Hippocampal place cells contribute to mammalian spatial navigation and memory formation. Numerous models have been proposed to explain the location-specific firing of this cognitive representation, but the pattern of excitatory synaptic input leading to place firing is unknown, leaving no synaptic-scale explanation of place coding. Here we used resonant scanning two-photon microscopy to establish the pattern of synaptic glutamate input received by CA1 place cells in behaving mice. During traversals of the somatic place field, we found increased excitatory dendritic input, mainly arising from inputs with spatial tuning overlapping the somatic field, and functional clustering of this input along the dendrites over ~10 µm. These results implicate increases in total excitatory input and co-activation of anatomically clustered synaptic input in place firing. Since they largely inherit their fields from upstream synaptic partners with similar fields, many CA1 place cells appear to be part of multi-brain-region cell assemblies forming representations of specific locations

Locomotory phenotypes associated with L-AChR<i>(gf)</i> expression require neuropeptide signaling.

<p>(<b>A</b>) Average body bends/min measured in liquid for the genotypes indicated. The strong locomotory defects of <i>egl-3</i> and <i>egl-21</i> mutants prevented analysis of L-AChR(<i>gf</i>) effects on agar (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004584#pgen.1004584.s003" target="_blank">Fig. S3A, B</a>). Mutation of <i>pkc-1</i> normalized the locomotor effects of L-AChR(<i>gf</i>) in both liquid and on agar (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004584#pgen.1004584.s003" target="_blank">Fig. S3C–E</a>). (<b>B</b>) Movement trajectories of wild type, L-AChR<i>(gf), nlp-12</i>;L-AChR<i>(gf)</i> animals as indicated. Each black line shows the trajectory of one animal monitored for 45 s on food. (<b>C</b>) Average body bend amplitude for the genotypes indicated. Each bar represents the mean (±SEM) of values calculated from recordings of at least 15 animals. For (A) and (C) ***, p<0.0001 by ANOVA with Sidak's post-hoc test. (<b>D</b>) Wide-field epifluorescent image of an adult animal expressing <i>nlp-12::SL2::mCherry</i>. The image is oriented with the head to the left. White rectangle: nerve ring. Arrow: DVA cell body. (<b>E</b>) Average body bend amplitude for the indicated genotypes and effects of DVA ablation (–DVA). Ablations were performed on L2 stage animals. Body bend amplitude was measured from recordings of young adult animals 2 days following laser ablation. Error bars indicate mean (±SEM) of at least 8 animals. ***, p<0.0001 student's t-test.</p