Short and long-term plasticity modulates the brain-wide interactions of the hippocampus: a combined electrophysiology-fMRI study

This thesis examines the functional connectivity of the hippocampus with the rest of the brain, with a focus on the neocortex. The hypothesis explored, in an animal model, is whether the frequency-dependent behaviour of certain brain connectivity relationships applies to hippocampal-neocortical connections. To encompass the temporal and spatial resolution necessary to do this, two main techniques are used in combination in most of the experimental work hereby presented: (1) electrophysiological recordings of local field potentials (LFPs), and (2) functional activity recordings of blood oxygenation level dependent (BOLD) signal using functional magnetic resonance imaging (fMRI). The main hypothesis is that the frequency-dependent behaviour of specific hippocampal synapses imposes the rules of extra-hippocampal activity propagation and hippocampal-neocortical interactions. The main discovery is that short and long-term plasticity modulates network activation, a finding suggesting a possible mechanism that could mediate the encoding and consolidation of memory traces. Chapters 1 to 3 introduce the vast literature review in which this project lies, and the general methods utilised. Chapter 4 (first experimental chapter) describes, using electrophysiology in rats, the evoked response of the main hippocampal output (CA1 neurons) when its major input (CA3 pyramidal cells) is activated at frequencies that in subsequent experiments were used to build brain-wide functional maps. CA1 spiking activity is found to be optimal in maintaining the amplitude of the population spike (PS) at beta frequencies (10-20 Hz), whereas lower (20 Hz) frequencies are normally less effective. Chapter 5 describes, using fMRI, how these intra-hippocampal activity patterns relate to long-range activity propagation in fMRI experiments. Hippocampal activation exhibits a linear monotonic increase with evoked frequency, whilst a network of selected structures is activated preferentially when beta frequencies are applied (mainly neocortical structures like the prefrontal and parietal cortices, motor and sensory cortices, and some subcortical structures like the nucleus accumbens and the striatum). This data is highly correlated with the PS recorded in CA1 and with multi-unit activity (MUA) and single-unit activity (SUA) simultaneously recorded in the medial prefrontal cortex (mPFC), one of the structures receiving propagated activity at beta frequencies, as described in Chapter 6. As mPFC also receives hippocampal input at a restricted beta frequency range stimulation of the dorsal hippocampus, Chapter 7 describes the use of a combined electrophysiology/fMRI approach to identify the pathway responsible for activity propagation. We performed microsurgery lesions to investigate the pathway responsible for the polysynaptic propagation of activity. Findings indicate that the septo-temporal longitudinal pathway is the one leading information transfer from dorsal to ventral hippocampus in the rat, and from there directly to the ventral subiculum, apparently by-passing entorhinal cortex. Last, in Chapter 8 the effect of durable modifications of synaptic weights by long-term potentiation (LTP) in the previously described frequency-dependent activity propagation is also described and contextualized in the memory trace consolidation framework, both electrophysiologically (Chapter 5) and with fMRI (Chapter 6). LTP is a long-lasting change in synaptic weights that, at the CA3-CA1 synapse, is capable of modifying hippocampal-neocortical connections such as to open the opportunity for higher frequency patterns (>40 Hz) to propagate to neocortical structures. These results suggest that, by means of frequency-coding, the hippocampus normally regulates propagation of selected information to the neocortex, but that at specific moments (e.g. when the hippocampus undergoes LTP) this regulation broadens to permit high-frequency information to pass through and affect neural activity in the cortex. It is a beautifully simple mechanism that merits further detailed examination in a multi-disciplinary manner as outlined in Chapters 9 and 10