BMS2011 Lecture 9 LeBeau 2024.pptx

NEUROSCIENCE: FROM CELLS TO COGNITION BMS2011 NEURONAL OSCILLATIONS FIONA LEBEAU [email protected] 2024 CORTICAL BRAIN RHYTHMS CORTICAL RHYTHMS OSCILLATIONS BRAIN WAVES...

NEUROSCIENCE: FROM CELLS TO COGNITION BMS2011 NEURONAL OSCILLATIONS FIONA LEBEAU [email protected] 2024 CORTICAL BRAIN RHYTHMS CORTICAL RHYTHMS OSCILLATIONS BRAIN WAVES SYNCHRONIZED ACTIVITY THE ELECTROENCEHPHALOGRAM - EEG Hans Berger 10 Hz alpha wave THE MAGNETOENCEPHALOGRAM (MEG) Voltage changes are accompanied by magnetic field changes. MEG - measures the magnetic field rather than electric fields. Tiny fields but no distortion. Keeps temporal resolution and improves the spatial resolution - < 1cm. THE ELECTROENCEHPHALOGRAM - EEG THE ELECTROENCEHPHALOGRAM - EEG Each trace corresponds to the recording of one electrode. Different patterns of activity can be detected. Traub et al 2001, Epilepsia 42: 153. Epileptic seizure  OSCILLATION FREQUENCY AND BRAIN STATE Different cortical states = different dominant frequency oscillations. Generally:- Active sensory processing, attention, memory = low amplitude, high frequency (small and fast). Inactive quiescence and sleep = high amplitude, low frequency (big and slow).  AWAKE EEG OSCILLATIONS Defined by the frequency - 1 Hz = 1 cycle of oscillation/sec e.g. gamma 40 Hz = 1000/40 = 25 ms interval between cycles. Power spectra - Fourier transform of the trace - give the frequency components of the activity. Ward - Trends in Cognitive Sci 7; 553- (2003)  DIFFERENT EEG SIGNALS Slow waves < 1 Hz Delta rhythms 0.5 - 4 Hz Deep sleep Theta 3-7 Hz Alpha 9 -11 Hz Spindles 8-15 Hz Beta 15 - 30 Hz Alert awake Low Gamma 30 – 60-80 Hz High gamma > 60/80-150 Hz Ultrafast > 100 Hz All involved in memory functions.  SPATIAL MEMORY IN HUMANS An MEG study – virtual water maze task. Use a joystick to navigate to the hidden platform. Navigation to the platform from different starting locations requires formation of a cognitive map from distal visual cues on the surrounding walls. Measure path length and escape latency to find the platform. Cornwell et al J Neurosci 28: 5983-5990 (2008) SPATIAL MEMORY IN RODENTS  THETA OSCILLATIONS AND SPATIAL MEMORY IN HUMANS 0 2.5 sec Time relative to trial onset Increased theta (4-8 Hz) in the hippocampus during goal-directed navigation – not during aimless movements (control). No change in any other frequency of oscillation. Cornwell et al J Neurosci 28: 5983-599  WHAT GENERATES THE EEG AND LOCAL FIELD POTENTIAL SIGNAL? The local mean field potential reflects the average behaviour of a large number of interacting neurons.  CORTICAL PYRAMIDAL CELLS Cortical surface Layer V or 5  WHAT GENERATES THE EEG SIGNAL? Extracellular electrode: Sinks and sources Dendrite EPSP Current must complete circuit Soma When activity is synchronous then these voltage changes are large enough to record from the scalp with the EEG recording.  WHAT GENERATES THE EEG SIGNAL? From: Bear, Connors and Paradiso Neuroscience Exploring the brain. SUMMATION (LOCAL SYNCHRONY) ESSENTIAL From: Bear, Connors and Paradiso Neuroscience Exploring the brain. HOW ARE RHYTHMS GENERATED? Basket cells Hestrin and Galaretta 2005  GENERATION OF GAMMA RHYTHMS GABA inhibition Interneuron depolarised – not coupled together - fast firing Both interneurons depolarised – coupled together - slower firing  Period (frequency) is determined by the time course of the IPSP.  Networks of interneurons synchronise via synapses and gap junctions.  GENERATION OF GAMMA RHYTHMS  Mechanism of hippocampal gamma frequency activity Extracellular gamma oscillation Carbachol or kainate Add excitation LFP = local field potential. A local EEG. 100μV 200msec APs in interneurons IPSPs in pyramidal cells Parvalbumin containing basket cell interneuron GENERATION OF GAMMA RHYTHMS Fundamental circuit similar in all cortical areas. Control of Sleep and Wakefulness (Brown RE et al. 2012) Physiological Reviews, 92 (3), pp. 1087-1187.  OPTOGENETICS TO INVESTIAGE GAMMA ACTIVITY Bidirectional control of neurons – can excite or inhibit neurons with light. Blue light depolarises cell and it fires. ChR2 - channel lets in NpHR halorhodopsin is a Cl- positive charge in response channel – responds to Yellow to blue light yellow light. hyperpolarises and stops firing.  OPTOGENETIC CONTROL OF NEURONS Parvalbumin interneurons A fast-spiking interneuron Channelrhodopsin only in the PV cells. Now we can control the different components of our gamma generating circuit. OPTOGENETIC GENERATION OF GAMMA OSCILLATIONS Increasing the power (mW) of the light pulse gives increasing power of gamma activity in the local field potential – from activation of FS interneurons only. (Cardin et al Nature 2009) THE EEG: WHAT ARE RHYTHMS GOOD FOR? Big Question: How do we process perceptions, emotions, memories that are distributed across different brain regions so easily? Local interactions - ~ 1cm - monosynaptic connections. Large-scale synchrony >1 cm - e.g. across hemispheres or cortical regions. Varela et al 2001  THE PREFRONTAL CORTEX PFC involved in executive functions such as memory, attention, goal-directed, planning. Human and primate - dorsolateral Rodent - medial prefrontal cortex prefrontal cortex  THE HIPPOCAMPUS The hippocampus in humans and animals is critical for memory functions. Human hippocampus Rat hippocampus But hippocampus and PFC need to talk to each other for normal function  RHYTHMS FOR NEURONAL SYNCHRONY? Control of spike timing. Action potentials timed to arrive at peak excitability - narrows time window for excitability. The red and green neuronal groups undergo coherent excitability changes so have effective communication. The black group undergoes excitability fluctuations but they are not coherent with the green group so communication does not occur. Cell damage – loss of synchrony – impaired cognitive function. “oscillations constitute excitability fluctuations” Fries et al 2005 GAMMA FREQUENCY OSCILLATIONS IN MEMORY  RHYTHMS FOR LEARNING AND MEMORY? Entorhinal cortex-hippocampus – beta/gamma coupling increased during task learning. No learning – no beta/gamma coupling. Igarashi Curr Opinion Neurobiol 2015  GAMMA OSCILLATIONS IN DISEASE? Deficits in gamma activity now linked to many diseases associated with cognitive dysfunction including:- - Alzheimer’s disease and other dementias - Schizophrenia - Autism Excitation Inhibition Many conditions now linked to E to I imbalance. In most diseases there is a loss of the PV.  ABNORMAL GAMMA ACTIVITY IN MODELS OF AD Transgenic AD mice Has abnormal Pyramidal beta amyloid cell spikes Network hyperactivity occurs during periods of reduced gamma. Remember – the pyramidal cell spikes are controlled by the inhibition. Verret et al (2012) Cell 149; 708-721 ABNORMAL GAMMA ACTIVITY IN MODELS OF AD Excitation Inhibition  ABNORMAL GAMMA OSCILLATIONS IN MODELS OF AD No change in mini IPSCs suggest normal GABA synapses. Decreased spontaneous IPSCs indicates activity-dependent GABA dysfunction. Verret et al (2012) Cell 149; 708-721  ABNORMAL PV INTERNEURONS Nav 1.1 – sodium channel expressed on PV interneurons. Decreased Nav 1.1 expression suggests decreased PV interneurons. Restored Nav 1.1 function lead to: -  interneuron activity. -  gamma activity. -  hypersynchrony. -  memory function. In other studies in dementia, schizophrenia and autism there are clear deficits in PV interneurons. Verret et al (2012) Cell 149; 708-721  RESTORING GAMMA OSCILLATIONS? Transgenic AD mice Stimulating the brain at gamma frequency activity reduced the levels of beta amyloid pathology. Channel rhodopsin to drive PV cells at 40 Hz Re-set E-I balance and prevent disease progression??? Starting clinical studies in patients.  RESTORING GAMMA OSCILLATIONS? Transgenic AD mice Stimulating the brain at gamma frequency activity did not reduce the levels of beta amyloid pathology. The debate goes on…… BRAIN RHYTHMS DURING SLEEP?  STAGES OF SLEEP – SLEEP ARCHITECUTRE Sleep is characterised by stages of - light sleep stage 1 and 2. - slow wave sleep (SWS) – occurs in stage 3 and 4. - rapid eye movement sleep (REM) and non-REM. In humans early part of sleep mainly SWS - later periods get REM sleep Diekelmann and Born Nature Neurosci Reviews 11; 114-126 (20 STAGES OF HUMAN SLEEP Sleep and normal sleep rhythms are essential for cognitive function. Also changes in sleep occur in many diseases e.g. Alzheimer’s disease. Spindles ~8-15 Hz Fast spindles 12-15 Hz Critical for memory Slow oscillations < 1 Hz  WHAT IS SLEEP FOR? Developed the “two stage model” of memory consolidation: During consolidation newly encoded memory traces are reactivated in the fast learning store and that then drives the slow learning store. Representations in the slow learning store are gradually strengthened. Fast learning store = hippocampus Slow learning store = neocortex. Diekelmann and Born SLOW WAVE SLEEP OSCILLATIONS? 15; 217-223, 2020 DOWN Reactivation occurs during SWS. Synchronise large areas into UP widespread hyperpolarisation = “down state” - a period of neuronal silence, followed by an “up-state” with high firing rate.  IMPROVED LEARNING AFTER BOOSTING SLOW OSCILLATIONS Learn word pairs Transcranial stimulation. prior to sleep Boosting slow oscillations during sleep potentiates declarative memory performance. Measure the difference between learning and recall performance. Sleep improves recall in sham but greater increase with stimulation at 0.75 Hz not 5 Hz. Declarative task Procedural task Facts and events Motor skills Marshall et al Nature (2006) 444; 610-  SLOW OSCILLATIONS IN DISEASE Measured EEG activity in two bands:- - slow oscillations 0.5 – 1 Hz. White = - spindles 8 - 12 Hz. Sham Black = Stimulated Stimulation Sham Power in the 5 intervals between stimulation shows increased activity in (Hz) slow wave and spindle bands. This and other studies suggest slow oscillations are important for consolidation. Marshall et al. Nature (2006) 444; 610-  IMPROVING COGNITION IN HUMANS? So can slow stimulation improve cognition when its impaired? Patients with mild cognitive impairment (MCI). So-tDCS = slow transcranial direct current stimulation. Ladenbauer et al J. Neurosci. 32: 7111-7124 (2017) SLOW OSCILLATIONS IN HUMANS Slow oscillation (0.5 – 1 Hz) Slow oscillations Each patient got so-tDCS or sham stim 2 weeks apart during stage 2 sleep. Fast spindles Fast Ladenbauer et al J. Neurosci. 32: 7111-7124 (2017)  SLOW OSCILLATIONS IN HUMANS Stimulation improved visual recognition memory 9/15 improve 3/15 improve performance performance Ladenbauer et al J. Neurosci. 32: 7111-7124 (2017) SLOW OSCILLATIONS IN ALZHEIMER’S DISEASE SLOW OSCILLATIONS IN ALZHEIMER’S DISEASE Hanert et al 2024 SLOW OSCILLATIONS IN ALZHEIMER’S DISEASE Control – retention of the target location predicted by higher power spindles during sleep. No such correlation in patient group. Memory deficits correlated with reduced spindle power in patients with early AD.  NETWORK OSCILLATIONS SUMMARY - Oscillations reflect synchronised synaptic activity. - Different rhythms have different cellular mechanisms. - Different rhythms contribute to learning and memory in awake and sleep state. - Boosting oscillations can improve memory and maybe even reduce pathology. FROM MOLECULES TO NETWORK FUNCTION Studies suggest:- - Deficits in PV interneurons  deficits in gamma  deficits in memory. Understanding the circuit makes the design of drugs/techniques possible to try to boost oscillations and so improve cognitive function.  Matt Walker: Sleep is your superpower | TED Talk Published 2018