Chris J. Tinsley

Interfering with Fos expression in rat perirhinal cortex impairs recognition memory

Previous work has shown that immunohistochemical imaging of Fos protein is a reliable marker for changes in activity related to recognition memory in the perirhinal (PRH) cortex of the medial temporal lobe; however, whether PRH Fos expression is necessary for recognition memory had not been established. To investigate this potential requirement, antisense Fos oligodeoxynucleotide (ODN) was infused locally into PRH cortex to interfere with Fos production. As in previous studies, differential Fos expression produced by viewing novel or familiar visual stimuli was measured by immunohistochemistry: antisense Fos ODN infusion into PRH cortex disrupted the normal pattern of differential Fos expression in PRH cortex. The effect of antisense Fos ODN infusion into PRH cortex was therefore sought on recognition memory. Infusion before or immediately after acquisition impaired recognition memory for objects when the memory delay was 3 or 24 h, but not when the delay was 20 min, or when the ODN was infused before retrieval after a 24‐h delay. The findings indicate a role for Fos in consolidation processes underlying long‐term recognition memory for objects and establish that interfering with its expression impairs recognition memory. Antisense Fos ODN infusion also impaired object‐in‐place recognition memory. The results demonstrate that Fos is necessary for neuronal mechanisms in PRH cortex essential to recognition memory.

Contributions of area Te2 to rat recognition memory

Ablations and local intracerebral infusions were used to determine the role of rat temporal association cortex (area Te2) in object recognition memory, so that this role might be compared with that of the adjacent perirhinal cortex (PRH). Bilateral lesions of Te2 impaired recognition memory measured by preferential exploration of a novel rather than a familiar object at delays ≥20 min but not after a 5-min delay. Local infusion bilaterally into Te2 of (1) CNQX to block AMPA/kainate receptors or (2) lidocaine to block axonal transmission or (3) AP5, an NMDA receptor antagonist, impaired recognition memory after a 24-h but not a 20-min delay. In PRH all these manipulations impair recognition memory after a 20-min as well as a 24-h delay. UBP302, a GluK1 kainate receptor antagonist, impaired recognition memory after a 24-h but not a 20-min delay, contrasting with its action in PRH where it impairs only shorter-term (20 min) recognition memory. Also in contrast to PRH, infusion of the muscarinic receptor antagonist scopolamine was without effect. The Te2 impairments could not readily be ascribed to perceptual deficits. Hence, Te2 is essential for object recognition memory at delays >5 or 20 min. Thus, at long delays both area Te2 and PRH are necessary for object recognition memory.

A role for calcium-calmodulin-dependent protein kinase II in the consolidation of visual object recognition memory

The aim was to investigate the role of calcium‐calmodulin‐dependent protein kinase (CAMK)II in object recognition memory. The performance of rats in a preferential object recognition test was examined after local infusion of the CAMKII inhibitors KN‐62 or autocamtide‐2‐related inhibitory peptide (AIP) into the perirhinal cortex. KN‐62 or AIP infused after acquisition impaired memory tested at 24 h, indicating an involvement of CAMKII in the consolidation of recognition memory. Memory was impaired when KN‐62 was infused at 20 min after acquisition or when AIP was infused at 20, 40, 60 or 100 min after acquisition. The time‐course of CAMKII activation in rats was further examined by immunohistochemical staining for phospho‐CAMKIIThre286α at 10, 40, 70 and 100 min following the viewing of novel and familiar images. At 70 min, processing novel images resulted in more phospho‐CAMKIIThre286α‐stained neurons in the perirhinal cortex than did the processing of familiar images, consistent with the viewing of novel images increasing the activity of CAMKII at this time. This difference was eliminated by prior infusion of AIP. These findings establish that CAMKII is active within the perirhinal region between ∼20 and 100 min following learning and then returns to baseline. Thus, increased CAMKII activity is essential for the consolidation of long‐term object recognition memory but continuation of that increased activity throughout the 24 h memory delay is not necessary for maintenance of the memory.

The topology of connections between rat prefrontal, motor and sensory cortices

The connections of prefrontal cortex (PFC) were investigated in the rat brain to determine the order and location of input and output connections to motor and somatosensory cortex. Retrograde (100 nl Fluoro-Gold) and anterograde (100 nl Biotinylated Dextran Amines, BDA; Fluorescein and Texas Red) neuronanatomical tracers were injected into the subdivisions of the PFC (prelimbic, ventral orbital, ventrolateral orbital, dorsolateral orbital) and their projections studied. We found clear evidence for organized input projections from the motor and somatosensory cortices to the PFC, with distinct areas of motor and cingulate cortex projecting in an ordered arrangement to the subdivisions of PFC. As injection location of retrograde tracer was moved from medial to lateral in PFC, we observed an ordered arrangement of projections occurring in sensory-motor cortex. There was a significant effect of retrograde injection location on the position of labelled cells occurring in sensory-motor cortex (dorsoventral, anterior-posterior and mediolateral axes p < 0.001). The arrangement of output projections from PFC also displayed a significant ordered projection to sensory-motor cortex (dorsoventral p < 0.001, anterior-posterior p = 0.002 and mediolateral axes p < 0.001). Statistical analysis also showed that the locations of input and output labels vary with respect to one another (in the dorsal-ventral and medial-lateral axes, p < 0.001). Taken together, the findings show that regions of PFC display an ordered arrangement of connections with sensory-motor cortex, with clear laminar organization of input connections. These results also show that input and output connections to PFC are not located in exactly the same sites and reveal a circuit between sensory-motor and PFC.

Interfering with perirhinal brain-derived neurotrophic factor expression impairs recognition memory in rats.

The role of brain‐derived neurotrophic factor (BDNF) in recognition memory was investigated by locally infusing oligodeoxynucleotides (ODNs) into perirhinal cortex, a region of the temporal lobe essential for familiarity discrimination. Antisense but not sense BDNF ODN impaired consolidation of long‐term (24h) but not shorter‐term (20min) recognition memory.

The topology of connections between rat prefrontal and temporal cortices.

Understanding the structural organization of the prefrontal cortex (PFC) is an important step toward determining its functional organization. Here we investigated the organization of PFC using different neuronal tracers. We injected retrograde (Fluoro-Gold, 100 nl) and anterograde [Biotinylated dextran amine (BDA) or Fluoro-Ruby, 100 nl] tracers into sites within PFC subdivisions (prelimbic, ventral orbital, ventrolateral orbital, dorsolateral orbital) along a coronal axis within PFC. At each injection site one injection was made of the anterograde tracer and one injection was made of the retrograde tracer. The projection locations of retrogradely labeled neurons and anterogradely labeled axon terminals were then analyzed in the temporal cortex: area Te, entorhinal and perirhinal cortex. We found evidence for an ordering of both the anterograde (anterior-posterior, dorsal-ventral, and medial-lateral axes: p < 0.001) and retrograde (anterior-posterior, dorsal-ventral, and medial-lateral axes: p < 0.001) connections of PFC. We observed that anterograde and retrograde labeling in ipsilateral temporal cortex (i.e., PFC inputs and outputs) often occurred reciprocally (i.e., the same brain region, such as area 35d in perirhinal cortex, contained anterograde and retrograde labeling). However, often the same specific columnar temporal cortex regions contained only either labeling of retrograde or anterograde tracer, indicating that PFC inputs and outputs are frequently non-matched.

Using topographic networks to build a representation of consciousness

The subject of consciousness has intrigued both psychologists and neuroscientists for many years. Recently, following many recent advances in the emerging field of cognitive neuroscience, there is the possibility that this fundamental process may soon be explained. In particular, there have been dramatic insights gained into the mechanisms of attention, cognition and perception in recent decades. Here, simple network models are proposed which are used to create a representation of consciousness. The models are inspired by the structure of the thalamus and all incorporate topographic layers in their structure. Operation of the models allows filtering of the information reaching the representation according to (1) modality and/or (2) sub-modality, in addition several of the models allowing filtering at the topographic level. The models presented have different structures and employ different integrative mechanisms to produce gating or amplification at different levels; the resultant representations of consciousness are discussed.

Creating abstract topographic representations: implications for coding, learning and reasoning

Topographic maps are a fundamental and ubiquitous feature of the sensory and motor regions of the brain. There is less evidence for the existence of conventional topographic maps in associational areas of the brain such as the prefrontal cortex and parietal cortex. The existence of topographically arranged anatomical projections is far more widespread and occurs in associational regions of the brain as well as sensory and motor regions: this points to a more widespread existence of topographically organised maps within associational cortex than currently recognised. Indeed, there is increasing evidence that abstract topographic representations may also occur in these regions. For example, a topographic mnemonic map of visual space has been described in the dorsolateral prefrontal cortex and topographically arranged visuospatial attentional signals have been described in parietal association cortex. This article explores how abstract representations might be extracted from sensory topographic representations and subsequently code abstract information. Finally a simple model is presented that shows how abstract topographic representations could be integrated with other information within the brain to solve problems or form abstract associations. The model uses correlative firing to detect associations between different types of stimuli. It is flexible because it can produce correlations between information represented in a topographic or non-topographic coordinate system. It is proposed that a similar process could be used in high-level cognitive operations such as learning and reasoning.

Transforming bottom-up topographic representations with top-down signals in the brain

There has been considerable success in allocating function to the different parts of the brain. We also know much about brain organisation in different regions of the brain and how different brain regions connect to one another. One of the most important next steps for modern neuroscience is to work out how different areas of the brain interact with one another. In particular we need to know how sensory regions communicate with association areas and vice versa. This article explores how top-down signals originating from association areas may be used to process and transform bottom-up representations originating from sensory areas of the brain. Simple models of networks containing topographically organised ensembles of neurons used to integrate and process information are described. The different models can be used to process information in a variety of different ways that could be used as the starting point for a variety of cognitive operations, in particular the extraction of abstract information from sensory representations.

Differences in anatomical connections across distinct areas in the rodent prefrontal cortex

Prefrontal cortex (PFC) network structure is implicated in a number of complex higher‐order functions and with a range of neurological disorders. It is therefore vital to our understanding of PFC function to gain an understanding of its underlying anatomical connectivity. Here, we injected Fluoro‐Gold and Fluoro‐Ruby into the same sites throughout rat PFC. Tracer injections were applied to two coronal levels within the PFC (anterior +4.7 mm to bregma and posterior +3.7 mm to bregma). Within each coronal level, tracers were deposited at sites separated by approximately 1 mm and located parallel to the medial and orbital surface of the cortex. We found that both Fluoro‐Gold and Fluoro‐Ruby injections produced prominent labelling in temporal and sensory‐motor cortex. Fluoro‐Gold produced retrograde labelling and Fluoro‐Ruby largely produced anterograde labelling. Analysis of the location of these connections within temporal and sensory‐motor cortex revealed a consistent topology (as the sequence of injections was followed mediolaterally along the orbital surface of each coronal level). At the anterior coronal level, injections produced a similar topology to that seen in central PFC in earlier studies from our laboratory (i.e. comparing equivalently located injections employing the same tracer), this was particularly prominent within temporal cortex. However, at the posterior coronal level this pattern of connections differed significantly, revealing higher levels of reciprocity, in both temporal cortex and sensory‐motor cortex. Our findings indicate changes in the relative organization of connections arising from posterior in comparison to anterior regions of PFC, which may provide a basis to determine how complex processes are organized.