**3.8 Hippocampal activity and ORT**

The effects of these new compounds on learning and memory consolidation were investigated by hippocampal activity and in novel object recognition. Using the spectral analysis of the EEG, theta band (4-7 Hz) was directly recorded in rats by hippocampal depth electrode (Fig. 8). Theta oscillation was continuously monitored and recorded before and during exploration. In control animals, exploratory behaviour was correlated with an increase in hippocampal theta oscillation activity. In NBM-lesioned rats, no change in hippocampal theta frequency oscillations was observed during familial and novel recognition (Fig. 9).

Neural Basis of Object Recognition 17

Fig. 9. Quantitative changes in hippocampal theta (3 -7 Hz) activity (frequency in theta

§*p*<0.0001vs control and sham; #*p*<0.0001 vs NBM lesion and NBM lesion/saline.

Fig. 10. Correlation between ORT performance and Theta activity in neocortex and

hippocampus in rat subjected to NBM lesion.

Theta activity in hippocampus was significantly reduced in animals with disrupted NBM. Theta oscillation, in this group of rats, was restored after intraperitoneal injection of AC1 (12.5 mg i.p.). Data are expressed as percent change (mean + SEM); \**p*<0.0001 vs baseline; ;

oscillations) recorded during ORT exploration in rat with NBM lesion.

The hippocampal theta oscillation, recorded in NBM-lesioned animals during the task, increased after drug treatment. In fact, compared to NBM-lesioned and not treated group, NBM-lesioned animals, which received the cholinomimetics, showed a significant increase in the duration and number of episodes of hippocampal theta activity (increase in frequency of theta rhythm) (Fig. 8).

The amount in hippocampal theta oscillations was correlated to performance in novel exploration (Fig. 10).

Fig. 8. Hippocampal Theta Oscillation in rats during exploration in ORT.

A bipolar electrode, stereotaxically implanted, was directly inserted into the CA1 area of the hippocampus to permit EEG recording. Theta rhythm was recorded during exploration in ORT and oscillatory activity (frequency) was studied. **A.** Control rat (intact and sham operated); **B.** Intact rat treated with AC1; **C.** Rat with lesion of the NBM and **D.** NBM lesioned rat injected with AC1. AC1 (12,5 mg/kg i.p.); seven animals for each experiment.

16 Advances in Object Recognition Systems

The hippocampal theta oscillation, recorded in NBM-lesioned animals during the task, increased after drug treatment. In fact, compared to NBM-lesioned and not treated group, NBM-lesioned animals, which received the cholinomimetics, showed a significant increase in the duration and number of episodes of hippocampal theta activity (increase in frequency

The amount in hippocampal theta oscillations was correlated to performance in novel

Fig. 8. Hippocampal Theta Oscillation in rats during exploration in ORT.

A bipolar electrode, stereotaxically implanted, was directly inserted into the CA1 area of the hippocampus to permit EEG recording. Theta rhythm was recorded during exploration in ORT and oscillatory activity (frequency) was studied. **A.** Control rat (intact and sham operated); **B.** Intact rat treated with AC1; **C.** Rat with lesion of the NBM and **D.** NBM lesioned rat injected with AC1. AC1 (12,5 mg/kg i.p.); seven animals for each

of theta rhythm) (Fig. 8).

exploration (Fig. 10).

experiment.

Fig. 9. Quantitative changes in hippocampal theta (3 -7 Hz) activity (frequency in theta oscillations) recorded during ORT exploration in rat with NBM lesion.

Theta activity in hippocampus was significantly reduced in animals with disrupted NBM. Theta oscillation, in this group of rats, was restored after intraperitoneal injection of AC1 (12.5 mg i.p.). Data are expressed as percent change (mean + SEM); \**p*<0.0001 vs baseline; ; §*p*<0.0001vs control and sham; #*p*<0.0001 vs NBM lesion and NBM lesion/saline.

Fig. 10. Correlation between ORT performance and Theta activity in neocortex and hippocampus in rat subjected to NBM lesion.

Neural Basis of Object Recognition 19

deficits point to the frontal cortex and hippocampus as early targets of functional disruption

Alzheimer's disease is a progressive neurodegenerative disease for which no cure exists. Accordingly, there is a substantial need for new therapies that offer improved symptomatic benefit and disease-slowing capabilities. Therefore, although no cure for Alzheimer's disease are available presently, a large number of potential therapeutic interventions have emerged, designed to correct loss of cholinergic function. A few of these compounds have

Indeed, we addressed the question of how we could contribute to alleviate cognitive decline

Because human brain imaging cannot reveal the work of any brain structure at the level of individual neurons, EEG characteristics in animals may be used to predict central activity of drugs in humans. Clearly, such an approach can also be used if first a relation between EEG

In our opinion, EEG and object recognition well interface each other to study cognitive function in brain such as recognition and discrimination memory. To date, according to our experience, EEG and object recognition task still remain the best experimental approach to

The animal model of AD here presented was designed for assessing the pharmacological efficacy of original compounds, thought enhancing central cholinergic transmission, on object recognition task combined with the EEG study of neocortical and hippocampal activity. On basis of the data obtained, we believe that this Alzheimer's disease model could be reliable because a significant disturbance in attention was produced. Furthermore, results from qEEG and object recognition correlation confirm that. Moreover, cholinergic drug

Although we limit our experiments to a particular attention system, we believe that our results can be generalized to other system configurations. If this is indeed the case, more experimental testing would be required to verify this speculation, for example, a tools for

In conclusion, some remarks can be drown. First, we have considered the relationship between prefrontal cortex, important for working memory, and hippocampus processing information associated with object recognition. We then presented, evidence from electrophysiological, pharmacological and brain-imaging studies demonstrating that prefrontal cortex shows sustained activity during acquisition of information in working memory tasks; that indicates that this area maintains on-line representations of stimuli after they are removed. Furthermore, we discussed the possibility that the cholinergic basal forebrain cortex hippocampus network plays an essential role in working memory during the acquisition and maintenance of information, monitoring and manipulating the engaged novelty. Finally, we also proposed an innovative experimental model of AD which might be used to test new antidementia drugs; moreover, we reported data from our pilot study in which evidence for a contribute in this field of research have been produced.

confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease.

following loss of cholinergic neurons in the basal forebrain.

and memory performance can be found in animals.

measuring phasic ACh release in the hippocampus.

test pharmacological activity of potential new antidementia drugs.

treatment recovered functionality in that saliency-based brain region.

in Alzheimer's disease.

**A.** Table reporting data on performance of rats in novel object recognition. NBM lesioned animals lost the ability to discriminate between the object getting a lower discrimination index (DI) than control group. **B.** Correlation between EEG theta power, recorded from neocortex in NBM-lesioned rats, and learning performance in ORT task. Damage of the cholinergic area caused a robust increase in theta power and a lower DI. AC1, in this group of animals, produced a reduction in theta power correlated with a higher DI. There was an extremely significant correlation (*r*= 0.9278, *p*<0.0001) between theta power and DI. **C.** Correlation between performance in novel object recognition and hippocampal theta oscillation (frequency) in rat with NBM lesion. The frequency of theta activity correlates to cognitive deficits in NBM-lesioned animals. Animals subjected to NBM-lesion scored a lower DI than control and showed reduced frequency in theta oscillation. AC1 administration was able to reduce the impairment in novel object recognition and restore the hippocampal theta rhythm during ORT. Theta oscillation correlates with DI (*r* = 0.818; *p*<0,0001). ORT. Spearman correlation between theta power and oscillation activity during object exploration performance evaluated as DI. Data are expressed as mean + SEM (time (s) in object exploration). \*p<0.01 N vs F (two-tailed Student's *t*-test). p<0.001 vs intact-control and sham. **#**p<0.001 vs lesioned and not-treated and saline-treated (Tukey-Kramer test for multiple comparison). T2 = exploration session, DI = Discrimination index (N-F/N+F). F = exploration time. AC1 (12.5 mg/kg i.p.). In each set of experiments 7 animals were used.

In conclusion, this Alzheimer's model, likely to other models, in animals produced memory deficit, worsening in behavioural performance and failing discrimination in novel object; moreover, changes in the architecture of EEG is also generated, such a significant increase in EEG theta power. Another interesting finding, coming from such an approach, was that selective cholinergic lesions of the nucleus basalis impaired spatial learning in the Morris water escape task [Rispoli et al., 2004, 2006, 2008]. The deficit in attention, learning and memory, highlighted in this experimental AD, shows a close correlation between changes in cortex-hippocampus neuronal network and novelty recognition of objects. Indeed, like AD, in this experimental model, produced by selective bilateral lesion of the NBM, normal EEG activity and cognitive function are progressively restored after administration of drugs enhancing central cholinergic transmission.

In conclusion, taken together, the present data suggest that these new drugs are able to restore the cholinergic cortico-hippocampal functional connectivity.
