**3. Alzheimer's disease**

Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by progressive decline in memory and cognitive functions. AD is associated with a dramatic loss of cholinergic neurons in the basal forebrain; specifically, those emerging from the nucleus basalis magnocellularis (NBM) [Whitehouse et al., 1981, 1982]; that causes a marked hypofunction in cholinergic transmission mainly innervating the neocortex and, in a lesser degree, the hippocampus (Fig. 1) [Mesulam et al., 1983; Coyle et al., 1983; Francis et al., 1999]. As a consequence of loss of cholinergic neurotransmission, impairment of attention, learning and memory function is produced and, furthermore, many other behavioural and cognitive capacities are also affected [Bartus et al., 1982; Collerton, 1986; Everitt and Robbins, 1997; Mufson et al., 2003].

A correct input from NBM to neocortex is essential for brain mechanisms such as arousal, attention, learning as well as working memory; whereas input from septal cholinergic neurons to hippocampus results important in memory processes such as spatial navigation.

Fig. 1. Cholinergic transmission in brain.

From electrophysiological viewpoint, it is well known that basal cholinergic neurons can generate a spontaneous firing rate to control neocortical neurons; then neocortical activation generates desynchronization of electroencephalogram (EEG) and behavioural states related to alertness and attention [Rasmusson et al., 1994].

Neural Basis of Object Recognition 7

Moreover, evoked potentials (EPs) show great correspondence between different species. In fact, auditory stimuli reveal a strong correspondence between rats and humans [Sambeth et al., 2003, 2004]. In both species, the short latency EP components are related to the processing of the physical properties of a stimulus, whereas the later components are associated with more endogenous processing (e.g., the psychological processes involved in

A particular aspect fascinate researchers: how does brain encode novel experiences, which

Although brain imaging has given important functional information about brain learning

However, understanding of object recognition and its neural basis, it necessarily means to focus on a first-order question: how individual neurons represent individual memories. This has led to theoretical models of short-term memory such as sustained spiking activity by single neurons that typically reflects a single memorandum [Fuster and Alexander, 1971; Fuster and Jervey, 1982; Hopfield, 1995]. In other words, there is increasing evidence that information encoding may also depend on the temporal dynamics between neurons; for example, from relative spikes to rhythmic activity across the neural population generating local field potential (LFP) [Metha et al., 2002; Ninokura et al., 2003; Warden and Miller, 2007;

It is well documented that central cholinergic system plays a crucial role in cognitive functions; therefore, from an electrophysiological and neurochemical point of view, the integrity of the frontal cortex and hippocampus circuitry is essential for brain cognitive processes. In fact, it is well known that neuronal loss, following basal cholinergic degeneration, shows a close correlation with neuronal death in another vulnerable region of

Hippocampus is another brain area important for learning and memory and it exhibits relevant theta (4-7 Hz) frequency oscillations *in vivo* during behavioural activity. In fact, neural action can vary during different cognitive processes, becoming rhythmic during such a brain activity; in particular, in brain, hippocampal theta rhythmicity could contribute to learning and memory [Lee et al., 2005]. In rat, spatial memory is supported by interaction between hippocampus and cortical areas, frontal cortex mainly, which is critically involved in attention and learning [O'Keefe and Recce , 1993; Morris, 2001; Monosov et al., 2010].

Different studies indicate that hippocampus plays an essential role in novelty detection. These researches show that an important electrophysiological mechanism, by which hippocampus learn and discriminate objects in novelty detection, is the hippocampal theta activity [König et al., 1995]. Recently, new findings offer an insight into the mechanisms underlying hippocampal novelty detection stimulating new questions within the debate:

It was proposed a link between the hippocampal theta and the detection of novel contexts. Some authors reported that in rats, exposed to familiar and novel environments, the peak

**3.2 Theta oscillation underlies hippocampal novelty detection and learning** 

and memory, it cannot reveal how the brain works at level of individual neurons.

the stimulus event) [Sambeth et al., 2003].

the brain such as the hippocampus.

theta peak or theta power?

are the intricate neural basis of learning and memory?

Siegel et al., 2009; Kayser et al., 2009; Warden and Miller, 2010].

In patients with AD, the profound cognitive deficits, following loss of basal cholinergic neurons, is likely due to disrupted cortex-hippocampus neuronal network [Whitehouse e al., 1981; Coyle et al., 1983; Davies et al., 1987].

Although in the last decades there has been considerable progress in understanding the molecular and cellular changes associated with Alzheimer's disease, to date, treatment of AD is merely palliative. In fact, medication with cholinergic drugs can only alleviate clinical symptoms, even if recent fMRI studies have shown the importance of cholinesterase inhibitors (AChEIs) in treating AD [Miettinen et al., 2011].

The recent understanding in AD pathogenesis has resulted in identification of a large number of new possible drug targets. These targets include therapies that aim to prevent production or remove the amyloid-β protein that accumulates in neuritic plaques, to prevent the hyperphosphorylation and aggregation into paired helical filaments of the microtubuleassociated protein tau and, finally, to keep neurons alive and functioning normally.

On which basis can we build an experimental model of Alzheimer's disease?

Experimental approach to pathophysiological comprehension of human disease, as well as to new therapeutics, has ethical limitations in medicine. For this reason, design and development of acceptable *in vivo* experimental animal models is important in research.

However, many different experimental approaches and behavioral testing have been suggested to study learning and memory. In particular, neuropharmacological research, involved in discovery of new antidementia agents, needs good experimental models of disease as well as good behavioral tests, which are important to validate pharmacological activity of drugs.
