Hippocampal electrical stimulation disrupts associative learning when targeted at dentate spikes

Abstract

Key points Dentate spikes are fast fluctuations of hilar local‐field potentials that take place during rest and are thought to reflect input arriving from the entorhinal cortex to the hippocampus. During dentate spikes, neuronal firing in hippocampal input (dentate gyrus) and output (CA1/CA3) regions is uncoupled. To date, the behavioural significance of dentate spikes is unknown. Here, we provide evidence that disrupting the dentate spike‐related uncoupling of the dentate gyrus and the CA1/CA3 subregions for 1 h after training retards associative learning. We suggest dentate spikes play a significant role in memory consolidation. Abstract Hippocampal electrophysiological oscillations, namely theta and ripples, have been implicated in encoding and consolidation of new memories, respectively. According to existing literature, hippocampal dentate spikes are prominent, short‐duration (<30 ms), large‐amplitude (∼2–4 mV) fluctuations in hilar local‐field potentials that take place during awake immobility and sleep. Interestingly, previous studies indicate that during dentate spikes dentate gyrus granule cells increase their firing while firing of CA1 pyramidal cells are suppressed, thus resulting in momentary uncoupling of the two hippocampal subregions. To date, the behavioural significance of dentate spikes is unknown. Here, to study the possible role of dentate spikes in learning, we trained adult male Sprague–Dawley rats in trace eyeblink classical conditioning. For 1 h immediately following each conditioning session, one group of animals received hippocampal stimulation via the ventral hippocampal commissure (vHC) contingent on dentate spikes to disrupt the uncoupling between the dentate gyrus and the CA1 subregions. A yoked control group was stimulated during immobility, irrespective of brain state, and another control group was not stimulated at all. As a result, learning was impaired only in the group where vHC stimulation was administered contingent on dentate spikes. Our results suggest dentate spikes and/or the associated uncoupling of the dentate gyrus and the CA1 play a significant role in memory consolidation. Dentate spikes could possibly reflect reactivation and refinement of a memory trace within the dentate gyrus triggered by input from the entorhinal cortex.

KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels

“…Dentate spikes coincide with periods of stronger gamma-band activity coherence between hippocampus and cortex and are temporally correlated to the power of sharp-wave ripples (Headley et al, 2017). Because both dentate spikes (Nokia et al, 2017) and sharp-wave ripples (Girardeau et al, 2009) have been associated with memory consolidation in hippocampal-dependent learning, we predict KCC2 suppression in the pathology may impact cognitive performances through a combination of GABA-dependent and independent mechanisms. Our results suggest therapeutic strategies aiming to either restore neuronal chloride homeostasis by blocking NKCC1 function (Ben-Ari, 2017) and neuronal excitability by targeting leak potassium channels (Loucif et al, 2018) or to stabilize KCC2 membrane expression (Gagnon et al, 2013;Liabeuf et al, 2017) may best compensate for altered network activity and associated behavioral or cognitive deficits.…”

KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels

“…Since both dentate spikes 78 and sharp-wave ripples 79 have been associated with memory consolidation in hippocampal-dependent learning, we predict KCC2 suppression in the pathology may impact cognitive performances through a combination of GABA-dependent and -independent mechanisms. Our results suggest therapeutic strategies aiming to either restore neuronal chloride homeostasis by blocking NKCC1 function 57 and neuronal excitability by targeting leak potassium channels 80 , or to stabilize KCC2 membrane expression 25,32 may best compensate for altered network activity and associated behavioral or cognitive deficits.…”

Dentate spikes and learning: disrupting hippocampal function during memory consolidation can improve pattern separation

“…Bipolar stimulation electrodes were made of Formwar coated stainless steel dual-wire with a diameter of 100 µm and a tip separation of ~500 µm. For a detailed description of the surgery, please see (Nokia et al 2017).…”

“…On the contrary, the meaning of DSs for behavior is still largely unclear. A recent study from our group suggests DSs might be important for memory consolidation 3 (Nokia et al 2017): Disrupting DS-related silencing of hippocampal CA1 pyramidal cell firing consistently after the training session impaired the learning of trace eyeblink conditioning, a hippocampus-dependent pavlovian conditioning task (Kim et al 1995). Here, to further probe the importance of DSs for neural plasticity and behavior, we trained adult male Sprague-Dawley rats in hippocampus-dependent learning tasks probing spatial reference memory, pattern separation and temporal interval learning.…”

“…After each training session, during a period of supposed memory consolidation in rest or sleep, we either disrupted the neural processing that normally follows DSs, disrupted neural processing at random or let the neural activity take its normal course. For the disruption, we used electrical stimulation of the ventral hippocampal commissure (Nokia et al 2017). We expected disruption of DS-related neural processing to impair learning in all three tasks.…”