Update on temporal lobe-dependent information processing, in health and disease.

The past decade has been characterized by a lot of remodeling in the field of learning and memory. Both of them, often associated with neuronal oscillations, an emergent property of brain networks, are governed by temporal lobe (TL) functional connectivity. An impairment of oscillatory mechanisms indeed often leads to TL-dependent cognitive deficits. While the classical view assigned the TL a major role in spatial information processing, new theories rather confer to the TL a more general function in cognitive processes beyond space representation. The present review covers, both in humans and in animal models, (a) the updated role of the TL in cognitive processes, addressing current debates in the field and proposing a scenario on how TL structures cooperate in order to bind an integrated representation of afferent information, (b) the oscillatory mechanisms underlying these TL-dependent cognitive functions (theta, gamma, sharp wave ripples) and (c) how TL-dependent cognition is altered during temporal lobe epilepsy, proposing a scenario on how reorganized TL networks in TLE leads to rhythmopathies and cognitive deficits. Temporal lobe epilepsy (TLE) is a well-studied neurological disease. Patients do not only suffer from epileptic seizures but also from cognitive and behavioral deficits between their seizures called comorbidities. TLE animal models are therefore used to understand how and when these comorbidities arise and what their underlying mechanisms are.

Changes in interictal spike features precede the onset of temporal lobe epilepsy.

OBJECTIVE: One cornerstone event during epileptogenesis is the occurrence of the first spontaneous seizure (SZ1). It is therefore important to identify biomarkers of the network alterations leading to SZ1. In experimental models of temporal lobe epilepsy (TLE), interictal-like activity (ILA) precedes SZ1 by several days. The goal of this study was to determine whether ILA dynamics bore electrophysiological features signaling the impeding transition to SZ1. METHODS: Experimental TLE was triggered by pilocarpine- or kainic acid-induced status epilepticus (SE). Continuous electroencephalographic recordings were performed 7 days before and up to 40 days after SE. The amplitude and duration of the spike and wave components of interictal spikes were analyzed. RESULTS: Two types of interictal spikes were distinguished: type 1, with a spike followed by a long-lasting wave, and type 2, with a spike without wave. The number, amplitude, and duration of type 1 spikes started to decrease, whereas the number of type 2 spikes increased, several days before SZ1, reaching their minimum/maximum values just before SZ1. INTERPRETATION: The change in ILA pattern could constitute a predictive biomarker of SZ1. The mechanisms underlying these dynamic modifications and their functional impact are discussed in the context of the construction of an epileptogenic network.

Early cognitive comorbidities before disease onset: A common symptom towards prevention of related brain diseases?

Brain diseases are very heterogeneous; however they also display multiple common risk factors and comorbidities. With a paucity of disease-modifying therapies, prevention became a health priority. Towards prevention, one strategy is to focus on similar symptoms of brain diseases occurring before disease onset. Cognitive deficits are a promising candidate as they occur across brain diseases before disease onset. Based on recent research, this review highlights the similarity of brain diseases and discusses how early cognitive deficits can be exploited to tackle disease prevention. After briefly introducing common risk factors, I review common comorbidities across brain diseases, with a focus on cognitive deficits before disease onset, reporting both experimental and clinical findings. Next, I describe network abnormalities associated with early cognitive deficits and discuss how these abnormalities can be targeted to prevent disease onset. A scenario on brain disease etiology with the idea that early cognitive deficits may constitute a common symptom of brain diseases is proposed.

Early deficits in spatial memory and theta rhythm in experimental temporal lobe epilepsy.

Patients with temporal lobe epilepsy (TLE), the most common form of epilepsy in adults, often display cognitive deficits. The time course and underlying mechanisms of cognitive decline remain unknown during epileptogenesis (the process leading to epilepsy). Using the rat pilocarpine model of TLE, we performed a longitudinal study to assess spatial and nonspatial cognitive performance during epileptogenesis. In parallel, we monitored interictal-like activity (ILA) in the hippocampal CA1 region, as well as theta oscillations, a brain rhythm central to numerous cognitive processes. Here, we report that spatial memory was altered soon after pilocarpine-induced status epilepticus, i.e., already during the seizure-free, latent period. Spatial deficits correlated with a decrease in the power of theta oscillations but not with the frequency of ILA. Spatial deficits persisted when animals had spontaneous seizures (chronic stage) without further modification. In contrast, nonspatial memory performances remained unaffected throughout. We conclude that the reorganization of hippocampal circuitry that immediately follows the initial insult can affect theta oscillation mechanisms, in turn, resulting in deficits in hippocampus-dependent memory tasks. These deficits may be dissociated from the process that leads to epilepsy itself but could instead constitute, as ILA, early markers in at-risk patients and/or provide beneficial therapeutic targets.

Potential causes of cognitive alterations in temporal lobe epilepsy.

Spatial and non-spatial memories are key processes whereby we process our environment on a daily basis, coding space, time and items to form unique memories. Both types of memory involve distributed and complex temporal lobe (TL) networks. In this review, we will discuss potential causes of spatial and non-spatial memory deficits, taking the example of temporal lobe epilepsy (TLE), a widespread neurological disorder characterized by cognitive comorbidities, in both animal models and TLE patients. We will start by briefly introducing TLE, then highlight by which underlying mechanisms TLE impairs TL-dependent cognitive functions.

h channel-dependent deficit of theta oscillation resonance and phase shift in temporal lobe epilepsy.

I(h) tunes hippocampal CA1 pyramidal cell dendrites to optimally respond to theta inputs (4-12 Hz), and provides a negative time delay to theta inputs. Decreased I(h) activity, as seen in experimental temporal lobe epilepsy (TLE), could significantly alter the response of dendrites to theta inputs. Here we report a progressive erosion of theta resonance and phase lead in pyramidal cell dendrites during epileptogenesis in a rat model of TLE. These alterations were due to decreased I(h) availability, via a decline in HCN1/HCN2 subunit expression resulting in decreased h currents, and altered kinetics of the residual channels. This acquired HCN channelopathy thus compromises temporal coding and tuning to theta inputs in pyramidal cell dendrites. Decreased theta resonance in vitro also correlated with a reduction in theta frequency and power in vivo. We suggest that the neuronal/circuitry changes associated with TLE, including altered I(h)-dependent inductive mechanisms, can disrupt hippocampal theta function.

In vivo Recording Quality of Mechanically Decoupled Floating Versus Skull-Fixed Silicon-Based Neural Probes.

Throughout the past decade, silicon-based neural probes have become a driving force in neural engineering. Such probes comprise sophisticated, integrated CMOS electronics which provide a large number of recording sites along slender probe shanks. Using such neural probes in a chronic setting often requires them to be mechanically anchored with respect to the skull. However, any relative motion between brain and implant causes recording instabilities and tissue responses such as glial scarring, thereby shielding recordable neurons from the recording sites integrated on the probe and thus decreasing the signal quality. In the current work, we present a comparison of results obtained using mechanically fixed and floating silicon neural probes chronically implanted into the cortex of a non-human primate. We demonstrate that the neural signal quality estimated by the quality of the spiking and local field potential (LFP) recordings over time is initially superior for the floating probe compared to the fixed device. Nonetheless, the skull-fixed probe also allowed long-term recording of multi-unit activity (MUA) and low frequency signals over several months, especially once pulsations of the brain were properly controlled.

Olfactory classical conditioning in newborn mice.

Determining the behavioural phenotype of genetically altered mice is a valuable approach for elucidating the function of genes and their role in cognitive disorders. Methods for phenotyping newborn mice are scarce and generally confined to sensorimotor reflexes. Here, we describe a simple method for assessing associative abilities in newborn mice. We used a two-odour-choice classical conditioning paradigm in mice from the day of birth (post-natal age 0, P0) to P6. Acquisition required 20 trials: 10 trials during which the pups were placed over the conditioned stimulus (CS+) odour (lemon or peppermint) for 30s and simultaneously stroked gently with a paintbrush and 10 trials during which the pups were placed over the other odour (CS-) for 30s, without stroking. Then, the pups were subjected to five odour-preference trials to test for conditioning. This sequence of five trials was repeated after 5 and 24h to assess retention of the conditioned odour preference. During the immediate post-acquisition sequence, the pups spent significantly more time over the CS+ than over the CS- (p<0.0001). No extinction of the conditioned preference was observed during this test. No preference was observed after 5 or 24h, indicating that the conditioned response was promptly lost. Conditioning was effective as soon as P0-P1. Thus, conditioning may emerge in newborn mice sooner than previously reported. This paradigm is well suited to phenotyping of large samples of genetically altered mice and may shed light on the role for genes in paediatric cognitive impairments.