Anxiolytic Drugs and Altered Hippocampal Theta Rhythms: The Quantitative Systems Pharmacological Approach
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1 Anxiolytic Drugs and Altered Hippocampal Theta Rhythms: The Quantitative Systems Pharmacological Approach Péter Érdi Henry R. Luce Professor Center for Complex Systems Studies Kalamazoo College perdi/ and Institue for Particle and Nuclear Physics, Wigner Research Centre, Hungarian Academy of Sciences, Budapest
2 Content 1. Hippocampal Theta Rhythm 2. Neurological and Psychiatric Disorders as Dynamical Diseases 3. Septohippocampal Rhythm Generation and Pharamacological Control 4. The Quantitative Systems Pharmacological Approach: Goals Methods Preliminary Results 5. Specific Message: Search for Selective Anxiolytics
3 Hippocampal Theta Rhythm Slow, global rhythmic electrical activity of the hippocampus (4-10 Hz) associated with gamma frequency studied in anesthetized and non-anesthetized rats also found in human hippocampal formation Functional Roles Linked to mnemonic processes Used for landmark navigation, path integration Correlates to anxiety levels
4 Hippocampal Theta Rhythm Structural hierarchies of the hippocampus Hippocampal formation generates (top), controls (right), and uses (left, bottom) theta rhythm
5 Neurological and Psychiatric Disorders as Dynamical Diseases Alzheimer disease Migraine Normal Pathological Schizophrenia storage and recall of memory traces PFIZER Pharma GmbH 2005 E E State changes in attractor structure pathological attractors fixed point attractor State Parkinson disease periodic attractor Dynamical Dahlem and Chronicle, Neurobiology, 2004 diseases Anxiety Control Epilepsy 3 20? ADHD 1 mv 3 sec. Power Power Frequency Reboxetine (0.3 mg/kg, IV) Frequency Hz Hz Events (Hz) Events (Hz) Time seconds Time seconds
6 Neurological and Psychiatric Disorders as Dynamical Diseases The theory of dynamical diseases emerged from chaos theory Dynamical disease occurs due to the impairment of the control system: associated to abnormal dynamics Develop realistic mathematical models and study effects of parameter changes Neurobiological interpretation Integration of molecular, cellular and system neuroscience Therapeutic strategies
7 Septohippocampal Rhythm Generation and Pharamacological Control SEPTOHIPPOCAMPAL SYSTEM THETA RHYTHM SKELETON NETWORK i (b) pyr i (O LM) i (S) KNOCK IN, KNOCK OUT TECHNIQUES MS GABA DESENSITIZATION KINETICS RECEPTOR SUBUNITS GABA SYNAPSE
8 Septohippocampal Rhythm Generation and Pharamacological Control Skeleton network of the septo-hippocampal system used to model rhythm generation and control by pharmacological means. The model consists of four cell populations: pyramidal cells of the hippocampal CA1 region (CAlp), stratum oriens interneurons (IO-LM), basket interneurons (IB) and septal GABAergic cells (Isept). g syn modified to simulate anxiolytics
9 Septohippocampal Rhythm Generation and Pharamacological Control
10 Specific message: Search for selective anxiolytics Towards a computational/physiological molecular screening and drug discovery Desired temporal pattern Nontrivial e.g. theta: enhanced cognition anxiogenics Septohippocampal system Temporal pattern Comp. computational & pharmaceutical modulation interface to further testing INTEGRATING SYSTEM and MOLECULAR LEVELS
11 Septohippocampal Rhythm Generation and Pharamacological Control Remarkable analogy between Type I (mobile) and Type II (immobile) theta frequency changes in animals linear relationship between frequency and running speed/reticular stimulation linear relationship affected similarly by anxiolytics Anxiolytics reduce stimulus-frequency intercept for Type I theta (also atropine resistant), but intercept and/or slope for Type II (also atropine sensitive) Reduction of theta frequency in animals has no false positives or negatives in predicting efficacy of human GAD treatment to date
12 Septohippocampal Rhythm Generation and Pharamacological Control (McNaughton and Gray, 2000) The effects of anxiolytic drugs on reticular-elicited (100 Hz stimulation) theta activity. Increasing strength of reticular stimulation produces a linear increase in theta frequency. Compared to pre-drug, anxiolytic drugs (CDP5chlordiazepoxide; DZP5diazepam; ALP5alprazolam; AMY5amylobarbitone) reduced the frequency of theta. Drugs which act to block acetylcholine (ACh), serotonin (5HT), dopamine (DA) or noradrenaline (NA) do not have this effect.
13 Septohippocampal Rhythm Generation and Pharamacological Control NEW DATA! JNeurosci.2013May15; 33(20) : Novelty and anxiolytic drugs dissociate two components of hippocampal theta in behaving rats. Wells CE, Amos DP, Jeewajee A, Douchamps V, Rodgers J, O Keefe J, Burgess N, Lever C. - in freely moving rats, there is a broadly linear relationship between hippocampal theta frequency and running speed over the normal range of speeds - environmental novelty decreases slope, whereas ANXIOLYTIC DRUGS REDUCE INTERCEPT -Variation in slope predicted changes in spatial representation by CA1 place cells and novelty-responsive behavior - Variation in intercept predicted anxiety-like behavior.
14 Septohippocampal Rhythm Generation and Pharamacological Control a, b: Putative anxiolytic cannabinoid CB1 receptor agonist (O-2545) reduces intercept. c, d: Environmental novelty reduces its slope. Simultaneous drug and novelty reduces both intercept and slope independently (Wells et al., 2013)
15 The Quantitative Systems Approach: Goals simulate the effect of stimulating current to npo on theta frequency extend previous model with more realistic septal innervation study how chemically diverse anxiolytics modify synaptic parameters and reduce theta frequency (septal GABAergic and glutamatergic synapse modulation slope reduction?, cholinergic synapse modulation intercept reduction?)
16 The Quantitative Systems Approach: Methods Simulate effects of varying reticular stimulation on original model Implement additional septal innervation to conductance based model of hippocampal CA1 region Selectively modify cholinergic, glutamatergic, and GABAergic synaptic conductances and/or dynamics to simulate anxiolytic effects on stimulus-frequency graph Septohippocampal system modeled as five distinct neuron populations interacting to generate emergent theta rhythm
17 The Quantitative Systems Pharmacological Approach: Preliminary Results Power spectra of synthetic EEGs calculated from simulations of varying levels of depolarizing current stimulus to pyramidal cells; shown here are 600 pa (solid line), 625 pa (dashed line), 675 pa (dotted line), and 700 pa (double-dashed line).
18 The Quantitative Systems Pharmacological Approach: Preliminary Results Mean frequency of theta band oscillation (3-8 Hz) increases linearly with stimulus (number of simulations run per stimulus, n = 16). Error bars represent standard deviation. Linear regression yields a slope of Hz/pA and intercept R 2 = 0.93.
19 The Quantitative Systems Pharmacological Approach: Preliminary Results Increase of time constants for synaptically activated GABAergic ion channels by 2 to 3 orders of magnitude in model appears to consistently lower theta frequency for large stimulating currents (compared to line with original constants), but increases variability of frequency for smaller stimulating currents (number of simulations run per stimulus, n = 10, 750τ). Error bars represent standard deviation. Linear regression yields a slope of Hz/pA and intercept R 2 = 0.17.
20 Next + synaptic parameters + Extrachippocampal and intrahippocampal theta generators: resonance
21 Collaborators Colin Lever (Durham University, UK): motivation, data, interpretation Tibin T. John: simulations (Kalamazoo College, students: will be the first author) Tamás Kiss: Pfizer, Integrative and Circuit Neuroscience (Boston): general expert :-)
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