MAJOR INTERESTS
Independent life relies on memory. In nature, throughout the seasons, animals know where to cyclically find food and water, and which places to avoid, in order to survive. This involves mentally mapping, in place and time, the distribution of resources and threats, and storing it such that it's readable by brain structures controlling adaptive behavior. The simplicity of this realization contrasts with the complexity of the mechanisms supporting it. How does the brain store, update, retrieve, and use, the memory of spatial contexts?
Current evidence shows that hippocampus (HIPP) and adjacent entorhinal cortex (EC) form a complex circuit whose neurons change their activity depending on the position of the animal in space. This kind of spatial rate-mapping endures in time, and it's retrievable, constituting what is called the spatial memory engram. Reactivation of such memory engram would then make it available for use by the "executive" cingulate (ACC) and retrosplenial (RSC) regions (midline cortex, MC), whenever an animal needs such information for decision-making. Evidence for this model is largely correlative, scarcely causal. We do not know the mechanisms converting sensory information to EC-HIPP spatial-maps, nor those forming spatial memory engrams in EC-HIPP, neither how is it that "executive" brain areas such as MC retrieve and use spatial memory engrams to support behavioral choices.
To dissect the mechanisms linking sensory input, spatial memory, and decision-making, we will join cutting-edge techniques from multiple disciplines: a) Anatomical tracings in rodent models to identify the neural circuits connecting HIPP with MC, b) in vivo and in vitro electrophysiology, as well as optical recordings to investigate neural activity in these circuits during behavior, c) Fine manipulation of neural activity using genetically-encoded neural actuators (GENA), and d) Flexible behavioral protocols involving spatial memory and decision-making. Our approach will break new ground concerning the neural bases of mental functions, and pave the way for the development of new and more effective therapies of mental dysfunctions.
RESEARCH AREAS
While an animal performs a task (example below); the activity of the neurons involved will change systematically depending on behavior. Neurons that consistently exhibit distinct activity rates in distinct behavioral conditions are more informative of the animal’s behavior. In addition to this, inter-connected neurons from distinct regions of the brain will exhibit coordinated activity in parallel with distinct levels of behavioral information.
off the press...
Independent life relies on memory. In nature, throughout the seasons, animals know where to cyclically find food and water, and which places to avoid, in order to survive. This involves mentally mapping, in place and time, the distribution of resources and threats, and storing it such that it's readable by brain structures controlling adaptive behavior. The simplicity of this realization contrasts with the complexity of the mechanisms supporting it. How does the brain store, update, retrieve, and use, the memory of spatial contexts?
Current evidence shows that hippocampus (HIPP) and adjacent entorhinal cortex (EC) form a complex circuit whose neurons change their activity depending on the position of the animal in space. This kind of spatial rate-mapping endures in time, and it's retrievable, constituting what is called the spatial memory engram. Reactivation of such memory engram would then make it available for use by the "executive" cingulate (ACC) and retrosplenial (RSC) regions (midline cortex, MC), whenever an animal needs such information for decision-making. Evidence for this model is largely correlative, scarcely causal. We do not know the mechanisms converting sensory information to EC-HIPP spatial-maps, nor those forming spatial memory engrams in EC-HIPP, neither how is it that "executive" brain areas such as MC retrieve and use spatial memory engrams to support behavioral choices.
To dissect the mechanisms linking sensory input, spatial memory, and decision-making, we will join cutting-edge techniques from multiple disciplines: a) Anatomical tracings in rodent models to identify the neural circuits connecting HIPP with MC, b) in vivo and in vitro electrophysiology, as well as optical recordings to investigate neural activity in these circuits during behavior, c) Fine manipulation of neural activity using genetically-encoded neural actuators (GENA), and d) Flexible behavioral protocols involving spatial memory and decision-making. Our approach will break new ground concerning the neural bases of mental functions, and pave the way for the development of new and more effective therapies of mental dysfunctions.
RESEARCH AREAS
While an animal performs a task (example below); the activity of the neurons involved will change systematically depending on behavior. Neurons that consistently exhibit distinct activity rates in distinct behavioral conditions are more informative of the animal’s behavior. In addition to this, inter-connected neurons from distinct regions of the brain will exhibit coordinated activity in parallel with distinct levels of behavioral information.
off the press...
(Remondes, 2015, Cell Reports)
MAIN QUESTIONS
I currently hypothesize that fine cortico-hippocampal temporal coordination contributes to decision-making by regulating a flow of high-level sensory information, from hippocampus to neocortex, allowing cortex to encode available choices and their outcomes, and control behavior accordingly. To test this scenario I will focus on three unanswered questions:
I currently hypothesize that fine cortico-hippocampal temporal coordination contributes to decision-making by regulating a flow of high-level sensory information, from hippocampus to neocortex, allowing cortex to encode available choices and their outcomes, and control behavior accordingly. To test this scenario I will focus on three unanswered questions:
How do primary sensory inputs form complex spatial maps?
How are spatial maps stored in memory?
How are memories used to inform decisions?
Answering these questions involves thinking deeply about how neurons talk to each other, in order to generate hypothetical scenarios, and carefully plan experiments to test them. We are currently focusing on determining, and characterizing, what pathways connect the brain regions responsible for processing sensory inputs, and for their integration in memory and decision-making processes. As such, we record the neural activity from areas of the brain known (or hypothesized) to be involved in: The processing of multi-modal sensory input - medial occipital area 2 (Oc2M), storing spatial context - hippocampus and entorhinal cortex, processing of spatial contextual information in the service of cognitive control - the midline cortical areas, retrosplenial and anterior cingulate.
EXPERIMENTAL APPROACHES:
In goal-directed navigation an animal attributes value to memorized contextual elements such as places, as well as to other stimuli associated with reward. Such newly formed motivational context will condition the animals' future behavior, and also the recall of episodes in response to the presence of stimuli. Thus, the replay of past episodes during HIPP SWR should reflect this novel motivational significance, and interfering with the neurons involved in this process should lead to alterations in downstream neurophysiological events, and ultimately to behavioral deficits. To test our predictions within this framework, we will use: a) Behavioral tasks in which places and sensory cues condition performance. b) Large samples of neurons from candidate brain regions, monitored during behavior. c) Identified neuronal circuits connecting candidate brain regions. d) Precise control over neural activity in these circuits, to address their causal relevance for behavior.
Research on the neural basis of behavior has been limited by the lack of small and light devices, which can easily be implanted in the skull and carried by a rat with minimal disturbances. We will conduct neurophysiological recordings based on Open Source technologies, using a "hyperdrive" array of 30 independently movable recording tetrodes, surgically implanted in the rats’ skull, to acquire and digitize locally the neural signals from 2+ regions on each rat. Rat's position is permanently monitored through a professional-grade camera. All data is analyzed post-hoc to compute measures of neural coding, firing rate vs behavior variables (e.g. correct/incorrect choices and position occupied by the rat), measures of neural coordination such as correlation and coherence, measures of statistical causality such as Granger Causality, and neural coding using Bayesian Decoding Strategies.
Using metal electrodes to stimulate specific inputs to these circuits is not reliable due to off-target spread of electrical stimulation. To overcome such limitation we are injecting GENA at the appropriate sources, to stimulate thus targeted axon terminals locally at their destination. We can now select fresh coronal slices, and activate GENA at the desired input under visual guidance, while performing standard patch-clamp and extracellular recordings, to study the properties of specific synaptic inputs (input/output, frequency response, plasticity). Another limitation of in vitro electrophysiology is the impossibility of recording the responses of a region's whole microcircuitry. To overcome these limitations we are currently combining three techniques for the first time: fast fluorescent reporting of neural activity (with ~ms precision), light-sheet microscopy (LSM, recently acquired by iMM, to optically record from areas up to 5x5 mm), and GENA to stimulate specific neural inputs. This will result in an all-optical preparation under light-sheet microscopy, which will give us unprecedented access to the mechanisms of information processing at a "whole-microcircuit" level.
AS A RESULT, THIS IS WHAT WE DO IN OUR DAILY LAB LIFE:
-assembling mechanical and electronic mini-devices to perform state-of–the-art high density electrophysiological recordings from multiple single neurons, simultaneously at 2+ brain regions in the freely behaving rat,
-implementing behavioral protocols to assess learning and memory in the rat,
-virus injection-mediated delivery of ligand- or light-sensitive neural actuators (pharmaco- or optogenetics), to manipulate neuronal activity with second/millisecond precision using cerebral delivery of drugs, or light through an optic fiber.
-perfecting surgical techniques to implant these devices,
-developing mathematical and statistical methods to analyze multi-dimensional neural recording data, and implementing software routines.
-thinking and modeling…
EXPERIMENTAL APPROACHES:
In goal-directed navigation an animal attributes value to memorized contextual elements such as places, as well as to other stimuli associated with reward. Such newly formed motivational context will condition the animals' future behavior, and also the recall of episodes in response to the presence of stimuli. Thus, the replay of past episodes during HIPP SWR should reflect this novel motivational significance, and interfering with the neurons involved in this process should lead to alterations in downstream neurophysiological events, and ultimately to behavioral deficits. To test our predictions within this framework, we will use: a) Behavioral tasks in which places and sensory cues condition performance. b) Large samples of neurons from candidate brain regions, monitored during behavior. c) Identified neuronal circuits connecting candidate brain regions. d) Precise control over neural activity in these circuits, to address their causal relevance for behavior.
Research on the neural basis of behavior has been limited by the lack of small and light devices, which can easily be implanted in the skull and carried by a rat with minimal disturbances. We will conduct neurophysiological recordings based on Open Source technologies, using a "hyperdrive" array of 30 independently movable recording tetrodes, surgically implanted in the rats’ skull, to acquire and digitize locally the neural signals from 2+ regions on each rat. Rat's position is permanently monitored through a professional-grade camera. All data is analyzed post-hoc to compute measures of neural coding, firing rate vs behavior variables (e.g. correct/incorrect choices and position occupied by the rat), measures of neural coordination such as correlation and coherence, measures of statistical causality such as Granger Causality, and neural coding using Bayesian Decoding Strategies.
Using metal electrodes to stimulate specific inputs to these circuits is not reliable due to off-target spread of electrical stimulation. To overcome such limitation we are injecting GENA at the appropriate sources, to stimulate thus targeted axon terminals locally at their destination. We can now select fresh coronal slices, and activate GENA at the desired input under visual guidance, while performing standard patch-clamp and extracellular recordings, to study the properties of specific synaptic inputs (input/output, frequency response, plasticity). Another limitation of in vitro electrophysiology is the impossibility of recording the responses of a region's whole microcircuitry. To overcome these limitations we are currently combining three techniques for the first time: fast fluorescent reporting of neural activity (with ~ms precision), light-sheet microscopy (LSM, recently acquired by iMM, to optically record from areas up to 5x5 mm), and GENA to stimulate specific neural inputs. This will result in an all-optical preparation under light-sheet microscopy, which will give us unprecedented access to the mechanisms of information processing at a "whole-microcircuit" level.
AS A RESULT, THIS IS WHAT WE DO IN OUR DAILY LAB LIFE:
-assembling mechanical and electronic mini-devices to perform state-of–the-art high density electrophysiological recordings from multiple single neurons, simultaneously at 2+ brain regions in the freely behaving rat,
-implementing behavioral protocols to assess learning and memory in the rat,
-virus injection-mediated delivery of ligand- or light-sensitive neural actuators (pharmaco- or optogenetics), to manipulate neuronal activity with second/millisecond precision using cerebral delivery of drugs, or light through an optic fiber.
-perfecting surgical techniques to implant these devices,
-developing mathematical and statistical methods to analyze multi-dimensional neural recording data, and implementing software routines.
-thinking and modeling…