Typical information processing is thought to depend on the integrity of neurobiological oscillations that may underlie coordination and timing of cells and assemblies within and between structures. The 3–7 Hz bandwidth of hippocampal theta rhythm is associated with cognitive processes essential to learning and depends on the integrity of cholinergic, GABAergic, and glutamatergic forebrain systems. Since several significant psychiatric disorders appear to result from dysfunction of medial temporal lobe (MTL) neurochemical systems, preclinical studies on animal models may be an important step in defining and treating such syndromes. Many studies have shown that the amount of hippocampal 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 and attainment of asymptotic performance. Our lab has developed a brain–computer interface that makes eyeblink training trials contingent upon the explicit presence or absence of hippocampal theta. The behavioral benefit of theta-contingent training has been demonstrated in both delay and trace forms of the paradigm with a two- to fourfold increase in learning speed over non-theta states. The non-theta behavioral impairment is accompanied by disruption of the amplitude and synchrony of hippocampal local field potentials, multiple-unit excitation, and single-unit response patterns dependent on theta state. Our findings indicate a significant electrophysiological and behavioral impact of the pretrial state of the hippocampus that suggests an important role for this MTL system in associative learning and a significant deleterious impact in the absence of theta. Here, we focus on the impairments in the non-theta state, integrate them into current models of psychiatric disorders, and suggest how improvement in our understanding of neurobiological oscillations is critical for theories and treatment of psychiatric pathology.

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.

Eyeblink conditioning given in the explicit presence of hippocampal u results in accelerated learning and enhanced multipleunit responses, with slower learning and suppression of unit activity under non-u conditions. Recordings from putative pyramidal cells during u-contingent training show that pretrial u-state is linked to the probability of firing increases versus decreases rather than to the magnitude of such responses. These findings suggest that the learning facilitation during u may be due to the recruitment of additional neurons that increase their firing rate during trials.Rabbit eyeblink conditioning (EBC) is a well-characterized associative learning task that has provided crucial insights into the neurobiology of mammalian learning and memory (Christian and Thompson 2003). The hippocampus is necessary for trace EBC and displays both excitatory and inhibitory learning-related neural responses during behaviorally significant trial periods (Berger et al. 1983;Weiss et al. 1996; Disterhoft 1997, 1999). Hippocampal local field potentials (LFPs) are dominated in the rabbit by u, a 3-7 Hz oscillatory potential that is highly correlated with patterns of single-unit firing (Fox and Ranck 1981;Klausberger and Somogyi 2008). The mechanisms of u generation and its relationship to learning have been studied extensively (Buzsáki 2002;Colgin 2013). This includes its phasic coordination with extra-hippocampal network activity (Hyman et al. 2003;Siapas et al. 2005;Hoffmann and Berry 2009) and, when pretrial u-state is assessed, with the speed of behavioral learning (Berry and Thompson 1978;Nokia et al. 2008).The relationship between u and EBC has been confirmed in studies that disrupt hippocampal u via lesions or pharmacological inactivation to inhibit learning (Solomon et al. 1983;Salvatierra and Berry 1989;Kaneko and Thompson 1997) and in studies that elicit or enhance u to boost learning (Berry and Swain 1989). However, all of these studies produced unnatural (nonphysiological) alterations to the LFP, disrupting the natural ebb and flow that some believe to be essential to the role of u in cognitive processes (Buzsáki 2006;Berry and Hoffmann 2011). Importantly, Scarlett et al. (2004) cautioned that u induced by medial septum stimulation can profoundly distort the normal physiological response patterns in u-related hippocampal cells as well as their relation to the induced u LFP. Seager et al. (2002) developed a brain-computer interface to control the naturally occurring oscillations by restricting EBC trials to either the presence (T+) or absence (T2) of real-time hippocampal u, with animals in the T+ condition learning significantly faster than animals in the T2 condition. This finding has been replicated (Griffin et al. 2004;Asaka et al. 2005) and extended to show that T+ training leads to an increase in hippocampal multiple-unit responses (Griffin et al. 2004;Darling et al. 2011), reduction of age-related memory impairment (Asaka et al. 2005), enhancement in neural activity of the prefrontal cortex (Darling et ...

Theta rhythm is a 3-12 Hz oscillatory potential observed in the hippocampus during cognitive processes ranging from spatial navigation to learning. The 3-7 Hz range occurs during immobility and depends upon the integrity of cholinergic forebrain systems. The amount of pre-training theta in the rabbit strongly predicts the acquisition rate of classical eyeblink conditioning and impairment of this system substantially slows the rate of learning. Recent experiments utilized a brain-computer interface that makes eyeblink training trials contingent upon the explicit presence or absence of hippocampal theta. Power spectral ratios based on continuous sampling of hippocampal local field potentials were used to ensure that each trial was triggered during the appropriate theta state. One group received training during high theta and the other during very low theta. The results have been consistent and substantial-theta-contingent training produces a two-to four-fold increase in learning speed, accompanied by striking differences in hippocampal, prefrontal and cerebellar electrophysiological patterns. Unlike many interfaces that serve as sensory or motor prostheses, our system appears to engage cognitive resources that accelerate the rate of associative learning. One mechanism for this improvement might be better coordination of the phase relationships in the essential circuitry that includes cerebellum, hippocampus and medial prefrontal cortex, as well as brainstem nuclei necessary for the sensory and motor events during each trial. This chapter reviews such findings and proposes experiments that use this cognitive BCI to clarify the essential roles and coordination of structures in the distributed system that underlies eyeblink conditioning.