Jennifer J. Siegel

The Avian Hippocampus, Homing in Pigeons and the Memory Representation of Large-Scale Space

Abstract The extraordinary navigational ability of homing pigeons provides a unique spatial cognitive system to investigate how the brain is able to represent past experiences as memory. In this paper, we first summarize a large body of lesion data in an attempt to characterize the role of the avian hippocampal formation (HF) in homing. What emerges from this analysis is the critical importance of HF for the learning of map-like, spatial representations of environmental stimuli used for navigation. We then explore some interesting properties of the homing pigeon HF, using for discussion the notion that the homing pigeon HF likely displays some anatomical or physiological specialization(s), compared to the laboratory rat, that account for its participation in homing and the representation of large-scale, environmental space. Discussed are the internal connectivity among HF subdivisions, the occurrence of neurogenesis, the presence of rhythmic theta activity and the electrophysiological profile of HF neurons. Comparing the characteristics of the homing pigeon HF with the hippocampus of the laboratory rat, two opposing perspectives can be supported. On the one hand, one could emphasize the subtle differences in the properties of the homing pigeon HF as possible departure points for exploring how the homing pigeon HF may be adapted for homing and the representation of large-scale space. Alternatively, one could emphasize the similarities with the rat hippocampus and suggest that, if homing pigeons represent space in a way different from rats, then the neural specializations that would account for the difference must lie outside HF. Only future research will determine which of these two perspectives offers a better approximation of the truth.

The Homing Pigeon Hippocampus and Space: In Search of Adaptive Specialization

The hippocampus (HF) of birds and mammals is essential for the map-like representation of environmental landmarks used for navigation. However, species with contrasting spatial behaviors and evolutionary histories are likely to display differences, or ‘adaptive specializations’, in HF organization reflective of those contrasts. In the search for HF specialization in homing pigeons, we are investigating the spatial response properties of isolated HF neurons and possible right-left HF differences in the representation of space. The most notable result from the recording work is that we have yet to find neurons in the homing pigeon HF that display spatial response properties similar to HF ‘place cells’ of rats. Of interest is the suggestion of neurons that show higher levels of activity when pigeons are near goal locations and neurons that show higher levels of activity when pigeons are in a holding area prior to be being placed in an experimental environment. In contrast to the rat, the homing pigeon HF appears to be functionally lateralized. Results from a current lesion study demonstrate that only the left HF is sensitive to landmarks that are located within the boundaries of an experimental environment, whereas the right HF is indifferent to such landmarks but sensitive to global environmental features (e.g., geometry) of the experimental space. The preliminary electrophysiological and lateralization results offer interesting departure points for better understanding possible HF specialization in homing pigeons. However, the pigeon and rat HF reside in different forebrain environments characterized by a wulst and neocortex, respectively. Differences in the forebrain organization of pigeons and rats, and birds and mammals in general, must be considered in making sense of possible species differences in how HF participates in the representation of space.

Persistent activity in a cortical-to-subcortical circuit: bridging the temporal gap in trace eyelid conditioning

We have addressed the source and nature of the persistent neural activity that bridges the stimulus-free gap between the conditioned stimulus (CS) and unconditioned stimulus (US) during trace eyelid conditioning. Previous work has demonstrated that this persistent activity is necessary for trace eyelid conditioning: CS-elicited activity in mossy fiber inputs to the cerebellum does not extend into the stimulus-free trace interval, which precludes the cerebellar learning that mediates conditioned response expression. In behaving rabbits we used in vivo recordings from a region of medial prefrontal cortex (mPFC) that is necessary for trace eyelid conditioning to test the hypothesis that neurons there generate activity that persists beyond CS offset. These recordings revealed two patterns of activity during the trace interval that would enable cerebellar learning. Activity in some cells began during the tone CS and persisted to overlap with the US, whereas in other cells, activity began during the stimulus-free trace interval. Injection of anterograde tracers into this same region of mPFC revealed dense labeling in the pontine nuclei, where recordings also revealed tone-evoked persistent activity during trace conditioning. These data suggest a corticopontine pathway that provides an input to the cerebellum during trace conditioning trials that bridges the temporal gap between the CS and US to engage cerebellar learning. As such, trace eyelid conditioning represents a well-characterized and experimentally tractable system that can facilitate mechanistic analyses of cortical persistent activity and how it is used by downstream brain structures to influence behavior.

Hippocampus and homing in pigeons: left and right hemispheric differences in navigational map learning

One‐month‐old, inexperienced homing pigeons, prior to any opportunity to learn a navigational map, were subjected to either right or left unilateral ablation of the hippocampal formation (HF). These pigeons were then held together with a group of age‐matched control birds in an outdoor aviary, where they were kept for about 3 months with the opportunity to learn a navigational map. When subsequently tested for navigational map learning at about 4 months of age posthatching, control and right HF‐ablated pigeons were equally good at orienting homeward from distant, unfamiliar locations, indicating successful navigational map learning. By contrast, left HF‐ablated pigeons were impaired in orienting homeward, indicating a failure to learn a navigational map. Interestingly, both right and left HF‐ablated pigeons displayed impaired homing performance relative to controls. These results suggest that different aspects of homing pigeon navigation may be lateralized to different hemispheres, and in particular, the HF of the different hemispheres. The left HF appears critical for navigational map learning, i.e. determining an approximate direction home from distant, unfamiliar locations. The right HF, and possibly the left HF as well, appear to play an important role in local navigation near the loft, which is likely based on familiar landmarks.

Ultraflexible nanoelectronic probes form reliable, glial scar–free neural integration

Subcellular-sized, ultraflexible electrodes form seamless integration with the living brain and afford chronically reliable recording. Implanted brain electrodes construct the only means to electrically interface with individual neurons in vivo, but their recording efficacy and biocompatibility pose limitations on scientific and clinical applications. We showed that nanoelectronic thread (NET) electrodes with subcellular dimensions, ultraflexibility, and cellular surgical footprints form reliable, glial scar–free neural integration. We demonstrated that NET electrodes reliably detected and tracked individual units for months; their impedance, noise level, single-unit recording yield, and the signal amplitude remained stable during long-term implantation. In vivo two-photon imaging and postmortem histological analysis revealed seamless, subcellular integration of NET probes with the local cellular and vasculature networks, featuring fully recovered capillaries with an intact blood-brain barrier and complete absence of chronic neuronal degradation and glial scar.

Electrophysiological profile of avian hippocampal unit activity: A basis for regional subdivisions

Electrophysiological activity was recorded from single neurons (units) in the hippocampal formation (HF) of freely moving homing pigeons in order to provide a taxonomy of unit types found in the avian HF; a taxonomy that could be used to define regional subdivisions and be compared with unit types found in the mammalian hippocampus. Two distinct types of unit were observed in the avian HF. One type was uniformly characterized by relatively rapid firing rates and shorter spike widths, and was found throughout the HF. The other type was more variable in activity profile but, compared with the fast‐firing units, was characterized by slower firing rates and longer spike widths. However, despite the variable nature of the slow‐firing units, most slow‐firing units recorded within a given anatomical region displayed similar firing rates, spike widths, and interspike intervals. In general, ventral HF units displayed activity patterns similar to projection cells found in the mammalian Ammons horn. Most dorsocaudal units displayed activity patterns similar to presumed granular cells in the mammalian dentate gyrus. By contrast, most dorsorostral units displayed activity patterns similar to a type of unit found in the mammalian subiculum. Although different in some details, the overall activity profile of units found in the avian HF, and their regional distribution, is strikingly similar to unit types found in the mammalian hippocampus, suggesting that unit activity profile is one hippocampal dimension conserved through evolution. J. Comp. Neurol. 445:256–268, 2002.

Persistent Activity in Prefrontal Cortex during Trace Eyelid Conditioning: Dissociating Responses That Reflect Cerebellar Output from Those That Do Not

Persistent neural activity, responses that outlast the stimuli that evoke them, plays an important role in neural computations and possibly in processes, such as working memory. Recent studies suggest that trace eyelid conditioning, which involves a temporal gap between the conditioned and unconditioned stimuli (the trace interval), requires persistent neural activity in a region of medial prefrontal cortex (mPFC). This persistent activity, which could be conveyed to cerebellum via a pathway through pons, may engage the cerebellum and allow for the expression of conditioned responses. Given the substantial reciprocity observed among many brain regions, it is essential to demonstrate that persistent responses in mPFC neurons are not simply a reflection of cerebellar feedback to the forebrain, leaving open the possibility that such responses could serve as input to the cerebellum. This concern is highlighted by studies showing that hippocampal learning-related activity is abolished by cerebellar inactivation. We inactivated the cerebellum while recording single-unit activity from the mPFC of rabbits trained with a forebrain-dependent trace eyelid conditioning procedure. We report that, whereas the responses of cells that show an onset of increased spike activity during the trace interval were abolished by cerebellar inactivation, persistent responses that begin during the conditioned stimulus and persisted into the trace interval were unaffected. Therefore, conditioned stimulus-evoked persistent responses remain the strongest candidate input pattern to support the cerebellar expression of learned responses.

Trace Eyeblink Conditioning in Mice Is Dependent upon the Dorsal Medial Prefrontal Cortex, Cerebellum, and Amygdala: Behavioral Characterization and Functional Circuitry

Abstract Trace eyeblink conditioning is useful for studying the interaction of multiple brain areas in learning and memory. The goal of the current work was to determine whether trace eyeblink conditioning could be established in a mouse model in the absence of elicited startle responses and the brain circuitry that supports this learning. We show here that mice can acquire trace conditioned responses (tCRs) devoid of startle while head-restrained and permitted to freely run on a wheel. Most mice (75%) could learn with a trace interval of 250 ms. Because tCRs were not contaminated with startle-associated components, we were able to document the development and timing of tCRs in mice, as well as their long-term retention (at 7 and 14 d) and flexible expression (extinction and reacquisition). To identify the circuitry involved, we made restricted lesions of the medial prefrontal cortex (mPFC) and found that learning was prevented. Furthermore, inactivation of the cerebellum with muscimol completely abolished tCRs, demonstrating that learned responses were driven by the cerebellum. Finally, inactivation of the mPFC and amygdala in trained animals nearly abolished tCRs. Anatomical data from these critical regions showed that mPFC and amygdala both project to the rostral basilar pons and overlap with eyelid-associated pontocerebellar neurons. The data provide the first report of trace eyeblink conditioning in mice in which tCRs were driven by the cerebellum and required a localized region of mPFC for acquisition. The data further reveal a specific role for the amygdala as providing a conditioned stimulus-associated input to the cerebellum.

The effects of a changing ambient magnetic field on single-unit activity in the homing pigeon hippocampus

The central representation of geomagnetic information in the avian brain continues to challenge researchers. Although the homing pigeon hippocampal formation primarily participates in the map-like representation of landmarks, some suggestive data indicate that it may also participate in spatial behavior guided by geomagnetic information. Forty-four isolated neurons were recorded from the hippocampal formation of homing pigeons trained to shuttle between two goal locations under changing (direction and intensity, and direction only) magnetic field conditions. Of the 37 slow-firing cells sampled (<14 spikes/s), none displayed a change in firing rate at the time of magnetic field transitions or during different ambient magnetic field conditions. By contrast, three of seven fast firing cells (>17 spikes/s) clearly displayed a phasic increase in firing during at least one of the magnetic field transitions used. The results are consistent with the hypothesis that a subset of hippocampal formation neurons receives information regarding changes in the earths magnetic field that may be used to guide behavior.

Modification of persistent responses in medial prefrontal cortex during learning in trace eyeblink conditioning

Persistent spiking in response to a discrete stimulus is considered to reflect the active maintenance of a memory for that stimulus until a behavioral response is made. This response pattern has been reported in learning paradigms that impose a temporal gap between stimulus presentation and behavioral response, including trace eyeblink conditioning. However, it is unknown whether persistent responses are acquired as a function of learning or simply represent an already existing category of response type. This fundamental question was addressed by recording single-unit activity in the medial prefrontal cortex (mPFC) of rabbits during the initial learning phase of trace eyeblink conditioning. Persistent responses to the tone conditioned stimulus were observed in the mPFC during the very first training sessions. Further analysis revealed that most cells with persistent responses showed this pattern during the very first training trial, before animals had experienced paired training. However, persistent cells showed reliable decreases in response magnitude over the first training session, which were not observed on the second day of training or for sessions in which learning criterion was met. This modification of response magnitude was specific to persistent responses and was not observed for cells showing phasic tone-evoked responses. The data suggest that persistent responses to discrete stimuli do not require learning but that the ongoing robustness of such responses over the course of training is modified as a result of experience. Putative mechanisms for this modification are discussed, including changes in cellular or network properties, neuromodulatory tone, and/or the synaptic efficacy of tone-associated inputs.