Pretrial hippocampal θ-state differentiates single-unit response profiles during rabbit trace eyeblink conditioning

Abstract

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 ...

Hippocampal Non-Theta-Contingent Eyeblink Classical Conditioning: A Model System for Neurobiological Dysfunction

“…Utilizing the same four groups (T+, T−, T+ yoked, and T− yoked), Griffin et al ( 28 ) showed that T− animals required significantly more trials to reach early (fifth CR) and late (8/9 CRs) learning criteria, demonstrated a lower percentage of CRs on the first 4 days of training, and required more trials to reach fifth CR than their yoked control counterparts. These results have been replicated by our lab with T− animals reaching the fifth CR criterion later than T+ animals ( 146 , 147 ) and T− animals showing a lower percentage of CRs across the first 4 days of training ( 148 ). Taken together, the deficits seen in both delay and trace EBC mirror the patterns seen in patients and animal models of several psychiatric disorders.…”

“…Using our BCI, we have shown that training in the explicit absence of hippocampal theta produces deficits in EBC expected of a number of psychiatric conditions. Furthermore, these behavioral deficits are accompanied by electrophysiological disruptions at the LFP ( 147 , 148 ), multiple- ( 28 , 147 ), and single-unit ( 146 ) levels that are characteristic of conditions as disparate as schizophrenia, MDD, and AD. Of particular interest are the patterns seen across the regions necessary for EBC, with a lack of synchrony between hippocampus and cerebellum ( 148 ) and the absence of relevant response patterns in mPFC units ( 147 ).…”

“…Note that the T− condition is more heterogeneous than T+, with trials being triggered under both high delta and high alpha conditions. Figures created from data published in Cicchese et al ( 146 ).…”

“…To replicate this, our theta-triggered work was continued with single-unit recordings of hippocampal pyramidal cells. To determine whether changes in multiple-unit activity were caused by large firing rate changes in a few critical cells or by a change in the overall number of cells responding in a particular way (firing rate increasing or decreasing), Cicchese et al ( 146 ) analyzed pyramidal cell responses by their qualitative (rate increasing or decreasing) and quantitative (response magnitude) properties. Early in learning, putative pyramidal cells were more likely to decrease their firing rate during the tone period in T− than in T+ animals and more likely to increase their firing rate during both the tone and trace periods in T+ compared to T− (Figure 4 ).…”

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, ). Failures to replicate this effect may be due to presentation of the conditioning stimuli at a sub‐optimal phase of the theta cycle (Nokia, Waselius, Mikkonen, Wikgren, & Penttonen, ), hence an analysis of theta phase and phase resetting is important.…”