Recovery of Theta Frequency Oscillations in Rats Following Lateral Fluid Percussion Corresponds With a Mild Cognitive Phenotype.

Whether from a fall, sports concussion, or even combat injury, there is a critical need to identify when an individual is able to return to play or work following traumatic brain injury (TBI). Electroencephalogram (EEG) and local field potentials (LFP) represent potential tools to monitor circuit-level abnormalities related to learning and memory: specifically, theta oscillations can be readily observed and play a critical role in cognition. Following moderate traumatic brain injury in the rat, lasting changes in theta oscillations coincide with deficits in spatial learning. We hypothesized, therefore, that theta oscillations can be used as an objective biomarker of recovery, with a return of oscillatory activity corresponding with improved spatial learning. In the current study, LFP were recorded from dorsal hippocampus and anterior cingulate in awake, behaving adult Sprague Dawley rats in both a novel environment on post-injury days 3 and 7, and Barnes maze spatial navigation on post-injury days 8-11. Theta oscillations, as measured by power, theta-delta ratio, peak theta frequency, and phase coherence, were significantly altered on day 3, but had largely recovered by day 7 post-injury. Injured rats had a mild behavioral phenotype and were not different from shams on the Barnes maze, as measured by escape latency. Injured rats did use suboptimal search strategies. Combined with our previous findings that demonstrated a correlation between persistent alterations in theta oscillations and spatial learning deficits, these new data suggest that neural oscillations, and particularly theta oscillations, have potential as a biomarker to monitor recovery of brain function following TBI. Specifically, we now demonstrate that oscillations are depressed following injury, but as oscillations recover, so does behavior.

Medial septal stimulation increases seizure threshold and improves cognition in epileptic rats.

BACKGROUND: Temporal lobe epilepsy is most prevalent among focal epilepsies, and nearly one-third of patients are refractory to pharmacological intervention. Persistent cognitive and neurobehavioral comorbidities also occur due to the recurrent nature of seizures and medication-related side effects. HYPOTHESIS: Electrical neuromodulation is an effective strategy to reduce seizures both in animal models and clinically, but its efficacy to modulate cognition remains unclear. We hypothesized that theta frequency stimulation of the medial septum would increase septohippocampal oscillations, increase seizure threshold, and improve spatial learning in a rat model of pilocarpine-induced epilepsy. METHODS: Sham and pilocarpine rats were implanted with electrodes in the medial septum, hippocampus and prefrontal cortex. EEG was assessed days prior to and following stimulation. Sham and pilocarpine-treated rats received either no stimulation, continuous (throughout each behavior), or pre-task (one minute prior to each behavior) 7.7 Hz septal stimulation during the Barnes maze spatial navigation test and also during assessment of flurothyl-induced seizures. RESULTS: Both continuous and pre-task stimulation prevented epilepsy-associated reductions in theta oscillations over time. Additionally, both stimulation paradigms significantly improved spatial navigation in the Barnes maze, reducing latency and improving search strategy. Moreover, stimulation led to significant increases in seizure threshold in pilocarpine-treated rats. There was no evidence of cognitive enhancement or increased seizure threshold in stimulated sham rats. CONCLUSION: These findings have profound implications as theta stimulation of the septum represents a single frequency and target that has the potential to both improve cognition and reduce seizures for patients with refractory epilepsy.

Making Waves in the Brain: What Are Oscillations, and Why Modulating Them Makes Sense for Brain Injury.

Traumatic brain injury (TBI) can result in persistent cognitive, behavioral and emotional deficits. However, the vast majority of patients are not chronically hospitalized; rather they have to manage their disabilities once they are discharged to home. Promoting recovery to pre-injury level is important from a patient care as well as a societal perspective. Electrical neuromodulation is one approach that has shown promise in alleviating symptoms associated with neurological disorders such as in Parkinson's disease (PD) and epilepsy. Consistent with this perspective, both animal and clinical studies have revealed that TBI alters physiological oscillatory rhythms. More recently several studies demonstrated that low frequency stimulation improves cognitive outcome in models of TBI. Specifically, stimulation of the septohippocampal circuit in the theta frequency entrained oscillations and improved spatial learning following TBI. In order to evaluate the potential of electrical deep brain stimulation for clinical translation we review the basic neurophysiology of oscillations, their role in cognition and how they are changed post-TBI. Furthermore, we highlight several factors for future pre-clinical and clinical studies to consider, with the hope that it will promote a hypothesis driven approach to subsequent experimental designs and ultimately successful translation to improve outcome in patients with TBI.

Memory retrieval along the proximodistal axis of CA1.

The proximal and distal segments of CA1 are thought to perform distinct computations. Neurons in proximal CA1 are reciprocally connected with the medial entorhinal cortex (MEC) and exhibit precise spatial firing. In contrast, cells in distal CA1 communicate with the lateral entorhinal cortex (LEC), exhibit more diffuse spatial firing and are affected by the presence of objects in the environment. To determine if these segments make unique contributions to memory retrieval, we examined cellular activity along the proximodistal axis of CA1 using transgenic reporter mice. Neurons tagged during context learning in proximal CA1 were more likely to be reactivated during testing than those in distal CA1. This was true following context fear conditioning and after exposure to a novel environment. Reactivation was also higher in brain regions connected to proximal CA1 (MEC, distal CA3) than those connected to the distal segment (LEC, proximal CA3). To examine contributions to memory retrieval, we performed neurotoxic lesions of proximal or distal CA1 after training. Lesions of the proximal segment significantly impaired memory retrieval while damage to distal CA1 had no effect. These data suggest that context memories are retrieved by a hippocampal microcircuit that involves the proximal but not distal segment of CA1. © 2016 Wiley Periodicals, Inc.

Immediate-early gene transcriptional activation in hippocampus CA1 and CA3 does not accurately reflect rapid, pattern completion-based retrieval of context memory.

No studies to date have examined whether immediate-early gene (IEG) activation is driven by context memory recall. To address this question, we utilized the context preexposure facilitation effect (CPFE) paradigm. In CPFE, animals acquire contextual fear conditioning through hippocampus-dependent rapid retrieval of a previously formed contextual representation. Despite differences in behavior, we did not find any difference in CA1 or CA3 IEG activity associated with this rapid recall phase when comparing context preexposed and non-pre-exposed groups. These findings indicate that IEG activation in CA1 and CA3 is not an accurate readout of the neural activity associated with hippocampus-dependent rapid memory retrieval.

Cortical representations are reinstated by the hippocampus during memory retrieval.

The hippocampus is assumed to retrieve memory by reinstating patterns of cortical activity that were observed during learning. To test this idea, we monitored the activity of individual cortical neurons while simultaneously inactivating the hippocampus. Neurons that were active during context fear conditioning were tagged with the long-lasting fluorescent protein H2B-GFP and the light-activated proton pump ArchT. These proteins allowed us to identify encoding neurons several days after learning and silence them with laser stimulation. When tagged CA1 cells were silenced, we found that memory retrieval was impaired and representations in the cortex (entorhinal, retrosplenial, perirhinal) and the amygdala could not be reactivated. Importantly, hippocampal inactivation did not alter the total amount of activity in most brain regions. Instead, it selectively prevented neurons that were active during learning from being reactivated during retrieval. These data provide functional evidence that the hippocampus reactivates specific memory representations during retrieval.

Temporal dynamics of Arc gene induction in hippocampus: relationship to context memory formation.

Past studies have proposed a role for the hippocampus in the rapid encoding of context memories. Despite this, there is little data regarding the molecular processes underlying the stable formation of a context representation that occurs in the time window established through such behavioral studies. One task that is useful for investigating the rapid encoding of context is contextual fear conditioning (CFC). Behavioral studies demonstrate that animals require approximately 30 s of exploration prior to a footshock to form a contextual representation supporting CFC. Thus, any potential molecular process required for the stabilization of the cellular representation for context must be activated within this narrow and behaviorally defined time window. Detection of the immediate-early gene Arc presents an ideal method to assess the activation of specific neuronal ensembles, given past studies showing the context specific expression of Arc in CA3 and CA1 subfields and the role of Arc in hippocampal long-term synaptic plasticity. Therefore, we examined the temporal dynamics of Arc induction within the hippocampus after brief context exposure to determine whether experience-dependent Arc expression could be involved in the rapid encoding of incidental context memories. We found that the duration of context exposure differentially activated Arc expression in hippocampal subfields, with CA3 showing rapid engagement within as little as 3 s of exposure. By contrast, Arc induction in CA1 required 30 s of context exposure to reach maximal levels. A parallel behavioral experiment revealed that 30 s, but not 3 s, exposure to a context resulted in strong conditioned freezing 24 h later, consistent with past studies from other laboratories. The current study is the first to examine the rapid temporal dynamics of Arc induction in hippocampus in a well-defined context memory paradigm. These studies demonstrate within 30 s of context exposure Arc is fully activated in CA3 and CA1, suggesting that the engagement of plastic processes requiring Arc function (such as long-term potentiation) occurs within the same temporal domain as that required for behavioral conditioning.