Jamais vu all over again
What is the basis for the feeling that someplace or someone is familiar? Molas et al. have identified brain structures involved in signaling familiarity, a necessary element for the expression of preference for novelty.
Most of us have had the experience of encountering a person who looks familiar, yet we cannot recall having met. A related phenomenon is déjà vu, a vivid but inaccurate feeling that the current situation is familiar. This strong sense of familiarity occurs in the absence of any explicit evidence that the situation was previously encountered. Déjà vu is generally accepted to be a memory-based illusion resulting from a brief bout of anomalous activity in memory-related structures of the medial temporal lobe1. Jamais vu, sometimes regarded as the opposite of déjà vu, is the intense feeling that the current circumstances are novel and strange, despite the objective realization that they have indeed been previously experienced2. Both déjà vu and jamais vu occur in temporal lobe epilepsy3, as well as in normal individuals under ordinary situations. Compared with déjà vu, jamais vu is less common in normal populations and much more prevalent in some neuropsychiatric conditions; this difference in prevalence suggests that novelty and familiarity may be signaled by different brain pathways.
Molas et al.4 provide evidence explaining how we differentiate the new and strange from the old and familiar. They have identified a circuit in the midbrain that combines familiarity and novelty signals to allow the expression of novelty preference, a capacity exhibited by virtually all mammals that have been tested. Novelty preference and preferential exploration of novelty have yielded a number of tasks useful in the study of attention, perception, recognition, sociability and cognitive development. The novelty task, originally developed by Fantz5, has been used to study cognition in nonverbal subjects including chicks, rodents, nonhuman primates and infant humans.
Molas et al. employed two versions of the classic novelty task. The first is a social interaction test in which a mouse is first allowed to explore an empty pen and a pen holding an unfamiliar (or novel) juvenile demonstrator mouse (Fig. 1a, left). In the test phase, the subject mouse is presented with the now-familiar demonstrator mouse and a novel demonstrator mouse. Normal mice will explore the demonstrator mouse in preference to the empty pen and the novel demonstrator mouse in preference to the familiar demonstrator mouse. The second version of the novelty task is spontaneous object recognition (Fig. 1a, right). Here the mouse is presented with two identical objects in the study phase. In the test phase, the mouse is presented with a third copy of the familiar object along with a novel object. Normal mice will preferentially explore the novel object, demonstrating novelty preference.
Social and nonsocial recognition memory, as identified by the novelty task, rely on medial temporal lobe structures6–10, but processing information about novelty is also important for non-mnemonic cognitive functions. Dopaminergic areas in the midbrain, including the ventral tegmental area (VTA), are known to encode novelty11, but how novel items become familiar is not known. To address the issue of where familiarity signals emerge in the mammalian brain, the authors took a hint from zebrafish experiments in which social conflict resolution was found to rely on medial habenula (mHB) input to the interpeduncular nucleus (IPN)12. Molas et al. thought that the IPN and its input from mHB might be involved in signaling familiarity.
The authors began by testing mice in a version of the novelty task that involves social interaction (Fig. 1a, left). A subject mouse would actively investigate a novel demonstrator mouse, and investigation diminished as the demonstrator mouse became more familiar. When a second novel demonstrator mouse was presented, the subject mice showed rebound of social investigation. If the IPN is involved in signaling familiarity, then social familiarity should activate the IPN. Using expression of the immediate-early gene c-Fos as a proxy for neuronal activation, the authors found that IPN activation was much higher upon exposure to a familiar demonstrator mouse than upon exposure to a novel demonstrator mouse. The same results were observed with exposure to familiar objects (Fig. 1a, right). The authors next asked whether IPN activity increased with the degree of familiarity. Subject mice were exposed to the same demonstrator mouse once a day for up to 7 days. c-Fos increased progressively with successive encounters, peaking on the fifth day of exposure (Fig. 1b).
Interestingly, c-Fos was evident in IPN cells containing the neurotransmitter GABA. This suggests that IPN cells involved in signaling familiarity are largely inhibitory GABAergic interneurons (Fig. 1c,d). The authors hypothesized that the IPN inhibitory interneurons act as a brake for novelty-induced exploration. To test this, they used optogenetics, expressing a yellow-light-activated chloride pump, halorhodopsin, in the GABAergic interneurons of the IPN to enable optical suppression of the cells’ activity. Suppression of interneurons would be expected to increase overall IPN activity. Mice explored the demonstrator mouse for two consecutive days. On the third day, they were offered the choice between the familiar mouse and a novel mouse. For half the mice, yellow light was delivered to halorhodopsin-expressing IPN interneurons to suppress their activity (Fig. 1e, left). The other half of the mice served as controls and received no light. As expected, control mice explored the novel mouse much more than the familiar one. In contrast, the light-exposed mice explored the familiar mouse just as much as the novel one (Fig. 1e, right).
Next, the authors expressed channelrhodopsin-2, a blue-light-activated cation channel, in IPN inhibitory interneurons. Activation of interneurons should have had the effect of decreasing overall IPN activity (Fig. 1f, left). Photostimulation of the inhibitory IPN cells decreased subjects’ exploration of novel mice without changing exploration of familiar mice (Fig. 1f, right). Tests with inanimate objects paralleled results with social stimuli: photostimulation of the inhibitory IPN cells decreased subjects’ exploration of novel objects. Thus, when IPN interneurons are suppressed, overall IPN activity increases and exploration of familiarity increases. When IPN interneurons are activated, overall activity decreases and permits exploration of novel stimuli. The authors suggest that IPN interneurons act as a brake on the exploration of familiar stimuli, allowing the expression of novelty preference.
Finally, Molas et al. used optogenetic tools to modulate excitatory input to the IPN arising from the mHB and the VTA. These inputs were hypothesized to provide familiarity and novelty signals to the IPN, respectively (Fig. 1d). Photosuppression of the mHB terminals in the IPN increased exploration of familiar social and nonsocial stimuli without affecting exploration of novel stimuli (Fig. 1e, center left). Photostimulation of the mHB terminals in the IPN decreased exploration of novel social and nonsocial stimuli without affecting exploration of familiar stimuli (Fig. 1f, center and right). Next, the authors photostimulated the VTA dopaminergic terminals in the IPN. As in the phenomenon of jamais vu, this manipulation mimicked the novelty signal, resulting in increased exploration of a familiar mouse (Fig. 1e, center right). Interestingly, the photostimulation of dopamine terminals did not affect exploration of inanimate objects. Thus, the novelty signaling pathway may differ for social and nonsocial signals. The authors suggest that different subtypes of VTA dopaminergic neurons may mediate novelty responses to social and nonsocial stimuli.
It is tempting to conclude that novelty is simply the absence of memory-based familiarity. Yet a number of studies have provided evidence that the processing of novelty information and familiarity information can be functionally dissociated in the forebrain medial temporal lobe memory system. A study using c-Fos expression methods combined with structural equation modeling found evidence that, in rats presented with familiar objects, caudal perirhinal cortex activated the entorhinal-to-hippocampal field CA1 pathway, also known as the temporo-ammonic pathway13. When rats were presented with novel objects, perirhinal cortex activated the entorhinal-to-dentate gyrus pathway, also known as the perforant pathway. Another c-Fos study showed that exploration of a novel environment increased activation in the hippocampus, the prelimbic prefrontal cortex and the dopaminergic reward circuit14. Exploration of a familiar environment, however, increased activation in the amygdala. A better understanding of how the midbrain circuits interact with the forebrain circuits could help explain the human prevalence differences between déjà vu and jamais vu. Future work could elucidate other neural bases of neuropsychiatric disorders by explaining dysregulation of novelty and familiarity processing, depersonalization, derealization and other symptoms that involve detachment from familiar surroundings.
In this elegant series of experiments, Molas et al. have elucidated the mechanisms and circuitry by which novelty transitions to familiarity. A primary contribution of their work is the demonstration that novelty and familiarity are signaled by different pathways, partially overlapping in the IPN, to support novelty preference. These findings may explain why déjà vu and jamais vu contribute differently to symptom profiles of neuropsychiatric disorders. More importantly, the findings of Molas et al. have profound implications for understanding and treating neuropsychiatric disorders in which processing of novelty and familiarity are compromised.
отсюда: https://www.nature.com/neuro/journal/v20/n9/full/nn.4625.html