Harnessing the power of theta: natural manipulations of cognitive performance during hippocampal theta-contingent eyeblink conditioning

Abstract

Neurobiological oscillations are regarded as essential to normal information processing, including coordination and timing of cells and assemblies within structures as well as in long feedback loops of distributed neural systems. The hippocampal theta rhythm is a 3–12 Hz oscillatory potential observed during cognitive processes ranging from spatial navigation to associative learning. The lower range, 3–7 Hz, can occur during immobility and depends upon the integrity of cholinergic forebrain systems. Several studies have shown that the amount of pre-training theta in the rabbit strongly predicts the acquisition rate of classical eyeblink conditioning and that impairment of this system substantially slows the rate of learning. Our lab has used a brain-computer interface (BCI) that delivers eyeblink conditioning trials contingent upon the explicit presence or absence of hippocampal theta. A behavioral benefit of theta-contingent training has been demonstrated in both delay and trace forms of the paradigm with a two- to four-fold increase in learning speed. This behavioral effect is accompanied by enhanced amplitude and synchrony of hippocampal local field potential (LFP)s, multi-unit excitation, and single-unit response patterns that depend on theta state. Additionally, training in the presence of hippocampal theta has led to increases in the salience of tone-induced unit firing patterns in the medial prefrontal cortex, followed by persistent multi-unit activity during the trace interval. In cerebellum, rhythmicity and precise synchrony of stimulus time-locked LFPs with those of hippocampus occur preferentially under the theta condition. Here we review these findings, integrate them into current models of hippocampal-dependent learning and suggest how improvement in our understanding of neurobiological oscillations is critical for theories of medial temporal lobe processes underlying intact and pathological learning.

Astrocytic signaling supports hippocampal–prefrontal theta synchronization and cognitive function

“…Further experiments are needed to specifically address this issue. Together, these correlational evidences support the hypothesis that D-serine released by astrocytes modulates specifically basal theta synchronization, that may entrain unit or ensemble firing in anatomically connected cortical areas (Anderson et al, 2009;Benchenane et al, 2010;Hoffmann et al, 1957 et al, 2003). Nevertheless, due to the lack of literature and causal observations that support this hypothesis, further work is needed to address these open questions: (1) Does astrocyte signaling modulate simultaneously several ensembles of the septal-entorhinal-hippocampal circuit, i.e., is there a spatial modulation of the theta generation or its phase?…”

“…The expression of transgenes occurred throughout the brain, displaying a typical mosaic-like distribution (Figure 1d-i) (Florian, Vecsey, Halassa, Haydon, & Abel, 2011;Sultan et al, 2015). We consistently verified the astrocyte specificity of transgene expression, by performing immunofluorescence staining of brain slices containing the hippocampus and prefrontal cortex (regions of critical interest for this study (Gordon, 2011;Hoffmann, Cicchese, & Berry, 2015;Lima et al, 2014;Oliveira et al, 2013;O'Neill et al, 2013)), using specific antibodies to target GFP and astrocytic or neuronal markers. GFP-labeling revealed only structures with the characteristic bushy astrocytic morphology (Florian et al, 2011;Khakh & Sofroniew, 2015;Pascual et al, 2005).…”

“…Based on the available evidence linking dHIP-mPFC correct dialogue and cognitive processing (Anderson, Rajagovindan, Ghacibeh, Meador, & Ding, 2009;Benchenane et al, 2010;Hoffmann et al, 2015;Jones & Wilson, 2005;Oliveira et al, 2013;O'Neill et al, 2013;Siapas, Lubenov, & Wilson, 2005;Zhan, 2015), we hypothesized that the observed loss of dHIP-mPFC synchronization might underlie a cognitive loss in mice lacking astrocyte signaling. To address this idea, independent sets of mice were submitted to tasks that assess spatial learning and longterm memory consolidation (highly dependent on the interaction between the dHIP and mPFC), using different motivations (e.g., exploratory drive, or hunger) and different environments (e.g., water-free arenas) (Figure 3).…”

Differential responsivity of neurons in perirhinal cortex, lateral entorhinal cortex, and dentate gyrus during time‐bridging learning

“…Theta oscillations are also important in acquisition and retention of hippocampal‐dependent tasks (Hoffmann, Cicchese, & Berry, ; Takehara‐Nishiuchi et al, ). In fact, Berry et al reported that presenting trials when theta power is high results in faster learning of trace (or delay) EBC as compared with presenting trials when theta is not present (Cicchese, Darling, & Berry, ; Seager, Johnson, Chabot, Asaka, & Berry, ).…”

Cognitive Collaborations: Bidirectional Functional Connectivity Between the Cerebellum and the Hippocampus

“…For instance, while the process of pattern separation has been studied primarily within subregions of the hippocampal formation, it was recently reported that the cerebellum is also actively engaged during pattern separation tasks (Paleja et al, 2014 ). Conversely, tasks known to be heavily cerebellum-dependent can be significantly influenced by the hippocampus (Hoffmann and Berry, 2009 ; Wikgren et al, 2010 ; Hoffmann et al, 2015 ). A recognition of cerebellar-hippocampal interactions represents a paradigm shift as it challenges us to re-examine traditional notions of spatial and temporal processing and to better appreciate the collaborative efforts involved.…”