Laboratorio de Circuitos Neuronales

The image shows CA2 pyramidal neurons immunostained against PCP4 in magenta and α-Actinin2 in yellow. Cell nuclei are shown in cyan. Image taken by Elena Cid

Proximodistal organization of CA2

The proximodistal axis is considered a major organizational principle of the hippocampus. The CA2 region apparently breaks this rule. We discovered that CA2 is organized around the limit of the mossy fibers (Fernandez-Lamo et al., Cell Reports 2019). We found a characteristic molecular gradient within CA2 and marked proximodistal trends of synaptic activity and phase-locked theta and gamma firing.  Our data suggest that the structure and function of CA2 are distributed along the proximodistal hippocampal axis.

A deep CA1 pyramidal cell recorded and labeled in vivo by Ivan Fernandez-Lamo and processed by Elena Cid

Sublayer organization of CA1 replay

Recently, we discovered that deep and superficial CA1 pyramidal cells participate differentially during sharp-wave ripples (Valero et al Nat Neu 2015). Using unsupervised clustering of ripple events, we next disclosed a mechanism determining firing selectivity and its distorsion in the epileptic hippocampus (Valero et al. Neuron 2017). Our data support the idea of a strong regionalization of hippocampal function during basic processes underlying memory consolidation, which is a major research line today in our lab.

Using unsupervised clustering we disclosed variability of fast ripple waveforms. We found that the fast ripple power spectrum typically leakes into the high-frequency band, due to non-selective out-of-phase firing of CA1 pyramidal cells.

Mechanisms of epileptic fast ripples

Fast ripples are high-frequency oscillations (HFOs) >250 Hz recorded in epileptogenic hippocampal regions. In 2007, we proposed a mechanism by which fast ripples emerge from the pathological desynchronization of neuronal firing (Foffani et al. Neuron 2007). Later in 2010, we developed the out-of-phase firing hypothesis which is now accepted as a major mechanism of pathological HFOs (Ibarz et al. JNeurosc 2010). More recently, using unsupervised learning we disclosed synaptic mechanisms underlying firing selectivity collapse during fast ripples (Valero et al. Neuron 2017).

Upper image shows separation of excitatory and inhibitory conductances dominating threshold dynamics of population bursts. At bottom, the diagram shows equivalence of positive and negative feedback processes controlling threshold behavior in neurons and microcircuits

Population activity thresholds

Generation of population activities such as hippocampal sharp wave ripples and epileptiform discharges follows an emergent dynamics. During my postdoc, we discovered that population discharges are initiated at a threshold level of population firing after recovery from a previous event (de la Prida et al., Neuron 2016). Each population discharge follows an active buildup period when synaptic recruitment and cell firing increase to threshold levels. Firing of densely connected individual hub cells can advance the onset of population events by increasing population firing to suprathreshold values. We proposed a theoretical framework to understand sharp-wave ripple emergence.

Using paired intracellular recordings we studied the contribution of different cell types and microcircuits to immature population bursts known as Giant Depolarizing Potentials (GDPs). In the example, two different CA3 pyramidal cells fire and contribute distinctly to GDPs. More recently, the deep/superficial and proximodistal location of a diversity of cell types were identified as major axes for variability.

Ubiquity of immature population bursts

The idea of a critical period in hippocampal postnatal development characterized by hyperexcitability was a major research line in the 90s. Giant Depolarizing Potentials (GDPs) represent a prominent population event recorded in vitro and in vivo. During my PhD Thesis, I studied the microcircuit dynamics and cell type contribution to GDPs. They were considered to be generated in the CA3 hippocampal region. I discovered they were actually ubiquitous at any hippocampal area (Menendez de la Prida et al., EJN 1998), and generated by small pieces of tissue provided they contain a minimal network following a threshold dynamics (Menendez de la Prida, J Neurophysiol 1999; Physical Rev. E 1999). Using simultaneous intracellular recordings, I started exploring the contribution of different cell types to the initiation and triggering of population events (Menendez de la Prida and Sanchez-Andres, Neuroscience 2000).