Affective preclinical modeling of psychiatric disorders: taking imbalanced primal emotional feelings of animals seriously in our search for novel antidepressants

Abstract

Preclinical animal models of psychiatric disorders are of critical importance for advances in development of new psychiatric medicine. Regrettably, behavior-only models have yielded no novel targeted treatments during the past half-century of vigorous deployment. This may reflect the general neglect of experiential aspects of animal emotions, since affective mental states of animals supposedly cannot be empirically monitored. This supposition is wrong-to the extent that the rewarding and punishing aspects of emotion circuit arousals reflect positive and negative affective states. During the past decade, the use of such affective neuroscience-based animal modeling has yielded three novel antidepressants (i) via the alleviation of psychic pain with low doses of buprenorphine; (ii) via the amplification of enthusiasm by direct stimulation of the medial forebrain bundle); and (iii) via the facilitation of the capacity for social joy with play facilitators such as rapastinel (GLYX13). All have progressed to successful human testing. For optimal progress, it may be useful for preclinical investigators to focus on the evolved affective foundations of psychiatrically relevant brain emotional disorders for optimal animal modeling.

Keywords: antidepressant agent; buprenorphine; deep brain stimulation; emotional/affective behavior; medial forebrain bundle; primary process; secondary process; tertiary process.

Figure 1.. A summary of human brain arousals and inhibitions in humans experiencing four basic emotions (from autobiographical memory): Sadness (PANIC/GRIEF), Happiness (PLAY/JOY), anger (RAGE) and anxiety (FEAR) during positron emissions tomography (PET) scanning. Data are summarized in finer detail by Damasio et al. Distinct subcortical brain regions exhibit abundant arousals (reds and yellows) during each of these emotions, while there are abundant cortical inhibitions (reduced blood flow, coded as blues and purples) present in many cortical areas. To facilitate reading, upward arrows indicate increased brain arousals and downward arrows indicate reduced brain regional arousals. (The statistical “coarse kernel” data from Damasio et al were kindly provided by Antonio Damasio).

Figure 2.. Nested hierarchies of affective control within the brain: a summary of the hierarchical bottom-up and top-down (circular) causation that is proposed to operate in every brain primal emotional system. The schematic summarizes the evolutionary/developmental perspective that in order for higher mind-brain functions to mature and function (via bottom-up control) they have to be integrated with the lower brain-mind functions, with primary processes being depicted as squares (red: SEEKING level), secondary-process learning as circles (green: “wanting” level of analysis), and tertiary processes (blue “surprise” and “reward prediction” level of analysis,) as rectangles. This aims to convey the manner in which bottom-up evolution of nested hierarchies can integrate lower brain functions with higher brain functions to eventually exert top-down regulatoty control. Bottom-up controls prevail in infancy and early-childhood development. Top-down controls mature in adolescence and are optimized especially in adulthood. Each emotional system has abundant descending and ascending components that work together in a coordinated fashion to generate various instinctual emotional behaviors as well as the raw feelings normally associated with those behaviors.

Figure 3.. The first schematic representation of the medial forebrain bundle, a massive two-way neural pathway, coursing through the lateral hypothalamus, interconnecting the central regions of the midbrain with higher brain limbic regions, as first illustrated by LeGros Clark in 1938. Large bilateral damage as indicated by the blue X produces a profound amotivational dysphoric state where animals do not initially eat or drink or explore, while deep brain stimulation, as highlighted by the red “jolt” can produce sustained exploration and investigation of objects, with persistent sniffing, which proves to be highly rewarding (however, those behaviors do not reflect any behavior seen as animals are consuming rewards, but rather behavioral states that anticipate and seek rewards). The periaqueductal gray (PAG) of the midbrain is highlighted; it is the brain area with the highest concentration of emotional systems in the brain, with the dorsal PAG being the most aversive brain area as monitored with punishing effects (with concentrated RAGE, FEAR, and PANIC systems). Deep brain stimulation (DBS) of the dorsal PAG can produce a sustained decrease in the enthusiasm of the medial forebrain bundle, which is an affective model of depression. For a more comprehensive summary of the connectivities of the dopamine-enriched medial forebrain bundle, see Figure 4. Anatomical abbreviations from rostral to caudal: OB, olfactory bulbs; OP, olfactory peduncle; PA, paraolfactory area; OT, olfactory tract; S, septal area; DB, diagonal band of Broca; A, anterior commissure; Ch, optic chiasm; Hyp, hypophisis (pituitary gland); M, mammillary bodies.

Figure 4.. Venn diagram of significantly changed genes by oligonucleotide microarray monitored changes in 1283 gene-expression patterns in the frontal and posterior cortex 1 and 6 h after half an hour of affectively completely positive rough-and-tumble play episodes in rats (as monitored by abundant 50 kHz ultrasonic vocalizations (USVs) indicative of positive affect (as measured by brain reward with deep brain stimulation), and essentially no 22 kHz USVs indicative of negative affect (as measured by brain aversive states). The insert at upper left indicates the kinds of measures that are abundant during play that are or objective indicators of playfulness. The left-hand Venn diagrams summarize regionaly unique significantly changed gene expression patterns in frontal (motor/executive) areas (120 genes) and posterior (sensory/perceptual) brain regions (187 genes) 1 hour following the half-hour play episode, with a total of 186 genes shared by anterior and posterior cortical areas (with the largest gene-expression change being that for insulin-like growth factor 1 (IGF-1), whose protein levels had declined 1 h following the play episode, suggesting active deployment of that growth factor during play. Only 17 genes remained significantly changed at 6 h after play, including IGF-1, whose protein product was now higher than normal, indicating that play facilitates synthesis of IGF-1. In any event these data guided our discovery that that the NR2B subunit mRNA and protein levels were upregulated in the frontal and posterior cortex as determined by qrtPCR and Western blot, and that play indicative positive hedonic USVs were increased by an agonist dose of our NR2B preferring glycine site partial agonist GLYX-13 (1 mg/kg), and decreased by the NR2B antagonist ifenprodil (3 mg/kg). For published summaries of these results, see references 53-57.

Figure 5.. Schematic diagrams of the lateral view of the dopamine-energized SEEKING system of the rat brain (with major connectivities of the key nodes of the medial forebrain bundle depicted in Figure 3). (A) Ascending projections of A10 DA (dopamine) neurons localized in the ventral-tegmental-area-innervating forebrain limbic regions, via the medial forebrain bundle, including frontal cortex, prefrontal cortex, caudate nucleus, and a major learning-related terminal region of ascending mesolimbic dopamine systems, the nucleus accumbens septi. (B) Caudal projections of the nucleus accumbens septi. (C) Diverse other afferent projections to the nucleus accumbens septi. (D) Rostrally converging and caudally projecting pathways onto the neurons of the ventral tegmental area, where SEEKING-system dopamine cells are concentrated. AMY, amygdala; BST, bed nucleus of stria terminalis; C, caudate-putamen; CC, corpus callosum; DB, diagonal band of Broca; DN, dentate nucleus; DR, dorsal raphe; ET, entopeduncular nucleus; FC, frontal cortex; HC, hippocampus; IC, inferior colliculus; LH, lateral hypothalamus; LPO, lateral preoptic area; MFB, medial forebrain bundle; MPR, mesopontine reticular nuclei; NAS, nucleus accumbens septi; OB, olfactory bulb; PAG, periaqueductal gray; PFC, prefrontal cortex; PN, parabrachial nucleus; SC, superior colliculus; SI, substantia innominata; SN, substantia nigra; TH, thalamus; VP, ventral pallidum. Adapted from Ref 37: Ikemoto S, Panksepp J. The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward seeking. Brain Res Rev. 1999;31:6-41. Copyright © Elsevier, 1999