Large-Scale Dynamics in the Mouse Neocortex underlying Sensory Discrimination and Short-Term Memory

Sensorimotor integration (SMI) is a fundamental process that allows for an advantageous interaction with the environment, in which key external stimuli are transformed into apt action. In mammals, SMI requires quick and synchronized activity across sensory, association and motor brain areas of the neocortex. In some situations, the key stimulus and its corresponding action are separated by a delay. In such scenario, behaviour-relevant information must be held in short-term memory (STM) until a cue signals the adequate context to transform it into action. This thesis aims to uncover key determinants of brain activity that underlie SMI with a STM component. The first chapter offers a general introduction to the work presented in this thesis. To understand the principles of SMI, I will follow an evolutionary approach. I will explain how during SMI information flows across sensory and association areas. I will also introduce STM and the neocortical areas involved in delay activity. Next, I will emphasize the different sensing and behavioural strategies that animals use to extract action-guiding information from the world. Finally, I will propose different behavioural paradigms to study SMI and STM. Once this foundation is laid, I will introduce the methodological approach of this thesis, in particular genetically-encoded calcium indicators and wide-field imaging. I will end this chapter by stating the specific aims of this thesis. The second chapter is a published manuscript in which I contributed during the first two years of my doctoral thesis work. We studied large-scale dynamics in mice trained to solve a tactile discrimination task with a STM component. We found that mice follow an active and/or passive strategy to solve this task, defined by the presence or absence of whole body movements during tactile stimulation. The movement strategy influenced ongoing brain activity, with higher and more widespread activity in active versus passive trials. Surprisingly, this influence continued into the STM period even in the absence of movements. Active trials elicited activity during the delay period in frontomedial secondary motor cortex. In contrast, passive trials were linked with activity in posterior lateral association areas (PLA). We found these areas to be necessary for task completion in a strategy-dependent manner

Nitric Oxide-Dependent LTD at Infralimbic Cortex

Dendritic calcium (Ca2+) spikes play a key role in the genesis of long-term synaptic plasticity. Although synaptic plasticity in the infralimbic cortex is critical for the extinction of fear-conditioned memory, the role of Ca2+-spikes in the induction of synaptic plasticity at this cortex has not been explored in depth. Here we show that Ca2+-spikes in layer 5 pyramidal neurons (L5 PNs) of the rat infralimbic cortex are crucial in the induction of long-term depression of the excitatory postsynaptic currents (EPSCs). The lack of effect on the postsynaptic currents evoked by puffing glutamate and the changes in the variance of the EPSC amplitude that paralleled its inhibition suggest that this LTD of the EPSCs is mediated presynaptically. However, its induction requires cytosolic calcium elevations because it is prevented when the recorded L5 PN is loaded with BAPTA. Moreover, it depends on the synthesis of nitric oxide (NO) because it is absent on slices incubated with nitric oxidase synthase inhibitor L-NAME. Therefore, Ca2+-spikes can trigger LTD of the ESPCs through the NO dependent presynaptic form of synaptic plasticity, thus providing a novel form of inducing synaptic plasticity at L5 PNs of the rat infralimbic cortexThis work was supported by grants from Ministerio de Ciencia e Innovación, Spain (MICINN; BFU2011-23522) and Ministerio de Economía y Competitividad, Spain (MINECO; BFU2013-43668-P and BFU2016-80802-P AEI/FEDER, UE) to Dr. D. Fernández de Sevilla, professor at the Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, UniversidadAutónoma de Madri

Estimating anisotropy directly via neural timeseries

An isotropic dynamical system is one that looks the same in every direction, i.e., if we imagine standing somewhere within an isotropic system, we would not be able to differentiate between different lines of sight. Conversely, anisotropy is a measure of the extent to which a system deviates from perfect isotropy, with larger values indicating greater discrepancies between the structure of the system along its axes. Here, we derive the form of a generalised scalable (mechanically similar) discretized field theoretic Lagrangian that allows for levels of anisotropy to be directly estimated via timeseries of arbitrary dimensionality. We generate synthetic data for both isotropic and anisotropic systems and, by using Bayesian model inversion and reduction, show that we can discriminate between the two datasets - thereby demonstrating proof of principle. We then apply this methodology to murine calcium imaging data collected in rest and task states, showing that anisotropy can be estimated directly from different brain states and cortical regions in an empirical in vivo biological setting. We hope that this theoretical foundation, together with the methodology and publicly available MATLAB code, will provide an accessible way for researchers to obtain new insight into the structural organization of neural systems in terms of how scalable neural regions grow - both ontogenetically during the development of an individual organism, as well as phylogenetically across species. Keywords: Anisotropy; DCM; Data fitting; Field theory; Lagrangian; Neuroimagin

Comparison between the employ of a multibeam echosounder on an unmanned surface vehicle and the traditional photo-grammetric as techniques for documentation and monitoring of shallow-water cultural heritage sites: A case of study in the Bay of Algeciras

Over the last few years, due to various climatic, anthropogenic, and environmental factors, a large amount of submerged heritage has been unearthed and exposed to deterioration processes in the Bay of Algeciras. These impacts can be more severe in shallow waters, where the cultural heritage is more vulnerable to natural and human-induced impacts. This makes it urgent to document cultural heritage at risk of disappearing using different techniques whose efficiencies in the archaeological record need to be determined and compared. For this purpose, we have documented a shipwreck in the Bay of Algeciras using two techniques: photogrammetry and a multibeam echosounder. The photogrammetric method consists of obtaining a 3D model from numerous photographs taken of an object or a site. The processing software creates three-dimensional points from two-dimensional points found in the photographs that are equivalent to each other. Multibeam echosounders are capable of providing side scan imagery information in addition to generating contour maps and 3D perspectives of the surveyed area and can be installed in an unmanned surface vehicle. As a result, we have obtained two 3D visualisations of the shipwreck, i.e., digital copies, that are being used both for the analysis of its naval architecture and for its dissemination. Through the comparison of the two techniques, we have concluded that while a multibeam echosounder provides a detailed digital terrain model of the seabed, photogrammetry performed by divers gives the highest resolution data on objects and structures. In conclusion, our results demonstrate the benefits of this combined approach for accurately documenting and monitoring shipwrecks in shallow waters, providing valuable information for conservation and management efforts.This research was funded by: (1) Ministry of Science and Innovation, Spain, through the project “Vulnerability of littoral cultural heritage to environmental agents: impact of climate change (VOLICHE)” (PID2020-117812RB-I00/AEI /10.13039/501100011033): (2) European Regional Development Fund (FEDER), EU, Interreg V-A Spain-Portugal program (POCTEP) 2014–2020, through the project “KTTSeaDrones” (0622-KTTSEADRONES-5-E). (3) 2014–2020 ERDF Operational Programme and the Department of Economy, Knowledge, Business and University of the Regional Government of Andalusia, Spain, through the project “Between the Pillars of Hercules, underwater archaeology of a privileged space. The Bay of Algeciras (HERAKLES)”. (FEDER-UCA18-107327

Conservation laws by virtue of scale symmetries in neural systems

In contrast to the symmetries of translation in space, rotation in space, and translation in time, the known laws of physics are not universally invariant under transformation of scale. However, a special case exists in which the action is scale invariant if it satisfies the following two constraints: 1) it must depend upon a scale-free Lagrangian, and 2) the Lagrangian must change under scale in the same way as the inverse time, . Our contribution lies in the derivation of a generalised Lagrangian, in the form of a power series expansion, that satisfies these constraints. This generalised Lagrangian furnishes a normal form for dynamic causal models–state space models based upon differential equations–that can be used to distinguish scale symmetry from scale freeness in empirical data. We establish face validity with an analysis of simulated data, in which we show how scale symmetry can be identified and how the associated conserved quantities can be estimated in neuronal time series

Sensory and Behavioral Components of Neocortical Signal Flow in Discrimination Tasks with Short-Term Memory

In the neocortex, each sensory modality engages distinct sensory areas that route information to association areas. Where signal flow converges for maintaining information in short-term memory and how behavior may influence signal routing remain open questions. Using wide-field calcium imaging, we compared cortex-wide neuronal activity in layer 2/3 for mice trained in auditory and tactile tasks with delayed response. In both tasks, mice were either active or passive during stimulus presentation, moving their body or sitting quietly. Irrespective of behavioral strategy, auditory and tactile stimulation activated distinct subdivisions of the posterior parietal cortex, anterior area A and rostrolateral area RL, which held stimulus-related information necessary for the respective tasks. In the delay period, in contrast, behavioral strategy rather than sensory modality determined short-term memory location, with activity converging frontomedially in active trials and posterolaterally in passive trials. Our results suggest behavior-dependent routing of sensory-driven cortical signals flow from modality-specific posterior parietal cortex (PPC) subdivisions to higher association areas

Behavioral Strategy Determines Frontal or Posterior Location of Short-Term Memory in Neocortex

The location of short-term memory in mammalian neocortex remains elusive. Here we show that distinct neocortical areas maintain short-term memory depending on behavioral strategy. Using wide-field and single-cell calcium imaging, we measured layer 2/3 neuronal activity in mice performing a whisker-based texture discrimination task with delayed response. Mice either deployed an active strategy-engaging their body toward the approaching texture-or passively awaited the touch. Independent of strategy, whisker-related posterior areas encoded choice early after touch. During the delay, in contrast, persistent cortical activity was located medio-frontally in active trials but in a lateral posterior area in passive trials. Perturbing these areas impaired performance for the associated strategy and also provoked strategy switches. Frontally maintained information related to future action, whereas activity in the posterior cortex reflected past stimulus identity. Thus, depending on behavioral strategy, cortical activity is routed differentially to hold information either frontally or posteriorly before converging to similar action. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 65971